Curcumin mediated down-regulation of αV β3 integrin and up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) in Erlotinib resistant SW480 colon cancer cells.

PubMed

Javadi, Samira; Rostamizadeh, Kobra; Hejazi, Jalal; Parsa, Maliheh; Fathi, Mojtaba

2018-02-01

Erlotinib is a potent, selective, and orally active inhibitor of the epidermal growth factor receptor, but the development of erlotinib resistance during chemotherapy can lead to treatment failure. To shed light on the erlotinib-resistant pathway, this study investigated the effect of combination therapy using curcumin- and erlotinib-loaded nanoparticles on the expression of α v β 3 integrin and pyruvate dehydrogenase kinase 4 (PDK4) in an erlotinib-resistant SW480 colon cancer cell line. An erlotinib-resistant SW480 colon cancer cell line was produced by long-term exposure to erlotinib. Curcumin-loaded Methoxy poly ethylene glycol Poly caprolactone (cur/mPEG-PCL) and erlotinib-loaded mPEG-PCL (erl/mPEG-PCL) micelles were provided using a single step nanoprecipitation method and used as combination therapy of resistant SW480 cancer cells. After that, gene expression levels of PDK4, αv, and β3 mRNA were determined by the semiquantitative reverse transcription-polymerase chain reaction. Protein levels of whole α v β 3 integrin were evaluated using the enzyme-linked immunosorbent assay method. In SW480 cell line, the IC50 of nonresistant and resistant cells was 87.6 ± 1.2 nM and 19.1 ± 0.14 μM, for erlotinib and it was about 21.8 and 30 μM for curcumin, respectively. Although PDK4 expression was not significantly different in resistant and nonresistant cells, its expression was up regulated (1.4 fold) in resistant cells by a combination therapy of cur/mPEG-PCL at a dose of 3 μM and erl/mPEG-PCL at a dose of 5 μM. β 3 mRNA and the protein level of whole α v β 3 integrin was significantly higher in resistant SW480 cells as compared with those in nonresistant cells. In terms of treatment, a combination of 6-μM cur/mPEG-PCL and 5-μM erl/mPEG-PCL down regulated β 3 gene expression 6.6-fold in resistant cells as compared with nonresistant cells. At the protein level, a combination of 3-μM-cur/mPEG-PCL and 10-μM erl/mPEG-PCL reduced α v β 3

[Functional impairment and radiologic fasciitis under erlotinib therapy].

PubMed

Osdoit, S; Wierzbicka, E; Guillet, G

2011-01-01

Targeted molecules are recent and valuable weapons in the management of certain cancers. Among them, erlotinib is an inhibitor of epidermal growth factor receptor approved in non-small lung cancer and pancreatic cancer after failure of first line treatment. Erlotinib is responsible for many cutaneous side effects. We report a case of acute symptomatic fasciitis that has occurred during erlotinib therapy. To our knowledge it is the first case described. A 56-year-old man was treated with erlotinib for a metastatic non-small lung adenocarcinoma. Shortly after the treatment by erlotinib was introduced, he had a severe acneiform rash resistant to doxycycline treatment. After a year of treatment, he presented intense pain in the legs with functional impairment. Medical imaging confirmed fasciitis. It regressed along with the rash after using strong topical corticosteroids during ten days. Besides bacterial fasciitis, inflammatory and oedematous fasciitis have varied aetiologies. The occurrence of a documented fasciitis during anti EGFR-therapy is original and raises the question of underlying mechanism. We suggest three pathophysiological mechanisms: spreading by contiguity; paraneoplastic fasciitis, or specific lesion of the fascia due to anti-EGFR. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer.

PubMed

Ochi, Nobuaki; Isozaki, Hideko; Takeyama, Masami; Singer, Jack W; Yamane, Hiromichi; Honda, Yoshihiro; Kiura, Katsuyuki; Takigawa, Nagio

2016-06-10

The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Acquired MET D1228V mutation and resistance to MET inhibition in lung cancer

PubMed Central

Bahcall, Magda; Sim, Taebo; Paweletz, Cloud P.; Patel, Jyoti D.; Alden, Ryan S.; Kuang, Yanan; Sacher, Adrian G.; Kim, Nam Doo; Lydon, Christine A.; Awad, Mark M.; Jaklitsch, Michael T.; Sholl, Lynette M.; Jänne, Pasi A.; Oxnard, Geoffrey R.

2016-01-01

Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped and understanding of mechanisms of resistance to MET TKIs is limited. Here we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib, responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET D1228V induces resistance to type I MET TKIs through impaired drug binding while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response. PMID:27694386

Extensive Drug Resistance Acquired During Treatment of Multidrug-Resistant Tuberculosis

PubMed Central

Cegielski, J. Peter; Dalton, Tracy; Yagui, Martin; Wattanaamornkiet, Wanpen; Volchenkov, Grigory V.; Via, Laura E.; Van Der Walt, Martie; Tupasi, Thelma; Smith, Sarah E.; Odendaal, Ronel; Leimane, Vaira; Kvasnovsky, Charlotte; Kuznetsova, Tatiana; Kurbatova, Ekaterina; Kummik, Tiina; Kuksa, Liga; Kliiman, Kai; Kiryanova, Elena V.; Kim, HeeJin; Kim, Chang-ki; Kazennyy, Boris Y.; Jou, Ruwen; Huang, Wei-Lun; Ershova, Julia; Erokhin, Vladislav V.; Diem, Lois; Contreras, Carmen; Cho, Sang Nae; Chernousova, Larisa N.; Chen, Michael P.; Caoili, Janice Campos; Bayona, Jaime; Akksilp, Somsak; Calahuanca, Gloria Yale; Wolfgang, Melanie; Viiklepp, Piret; Vasilieva, Irina A.; Taylor, Allison; Tan, Kathrine; Suarez, Carmen; Sture, Ingrida; Somova, Tatiana; Smirnova, Tatyana G.; Sigman, Erika; Skenders, Girts; Sitti, Wanlaya; Shamputa, Isdore C.; Riekstina, Vija; Pua, Kristine Rose; Therese, M.; Perez, C.; Park, Seungkyu; Norvaisha, Inga; Nemtsova, Evgenia S.; Min, Seonyeong; Metchock, Beverly; Levina, Klavdia; Lei, Yung-Chao; Lee, Jongseok; Larionova, Elena E.; Lancaster, Joey; Jeon, Doosoo; Jave, Oswaldo; Khorosheva, Tatiana; Hwang, Soo Hee; Huang, Angela Song-En; Gler, M. Tarcela; Dravniece, Gunta; Eum, Seokyong; Demikhova, Olga V.; Degtyareva, Irina; Danilovits, Manfred; Cirula, Anda; Cho, Eunjin; Cai, Ying; Brand, Jeanette; Bonilla, Cesar; Barry, Clifton E.; Asencios, Luis; Andreevskaya, Sofia N.; Akksilp, Rattanawadee

2014-01-01

Background. Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance. Methods. To assess the GLC's impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC. Results. In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16–.47) for XDR tuberculosis, 0.28 (.17–.45) for FQ, and 0.15 (.06–.39) to 0.60 (.34–1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07–.62) for acquired XDR tuberculosis and 0.23 (.09–.59) for acquired FQ resistance. Conclusions. Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards. PMID:25057101

Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.

PubMed

Elmeliegy, Mohamed A; Carcaboso, Angel M; Tagen, Michael; Bai, Feng; Stewart, Clinton F

2011-01-01

To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420. After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b(-/-), Abcg2(-/-), Mdr1a/b(-/-)Abcg2(-/-), and Abcc4(-/-)), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration-time data, and brain penetration (P(Brain)) was estimated by the ratio of ECF-to-unbound plasma area under concentration-time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers. P(Brain) in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 P(Brain) in Abcg2(-/-) and Mdr1a/b(-/-)Abcg2(-/-) mice were significantly higher than in wild-type mice. Mdr1a/b(-/-) mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells. Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms. ©2010 AACR.

Erlotinib versus Radiation Therapy for Brain Metastases in Patients with EGFR-Mutant Lung Adenocarcinoma

PubMed Central

Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas; Shi, Weiji; Riely, Gregory J.; Beal, Kathryn; Yu, Helena A.; Chan, Timothy A.; Zhang, Zhigang; Wu, Abraham J.

2017-01-01

Purpose/Objectives Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system (CNS), it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole-brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). Median OS for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median 35 vs. 26 months, p = .62), while patients treated with SRS had a longer OS compared with the erlotinib group (median, 64 months, p = .004). Median time to ICP was 17 months. There was a longer time to ICP in patients who received WBRT vs. erlotinib upfront (median 24 vs. 16 months, p = .04). Patients in the erlotinib or SRS group were more likely to fail intracranially as a component of first failure, while WBRT patients were more likely to fail outside the brain (p = .004). Conclusions The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison to a targeted biologic agent with known CNS activity. PMID:24679729

Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib.

PubMed

Liu, Yutao; Li, Yan; Ou, Qiuxiang; Wu, Xue; Wang, Xiaonan; Shao, Yang W; Ying, Jianming

2018-04-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are promising targeted therapies for EGFR-mutated non-small-cell lung cancer (NSCLC) patients. However, acquired resistance inevitably develops. Comprehensive and dynamic companion genomic diagnosis can gain insights into underlying resistance mechanisms, thereby help oncologists and patients to make informed decision on the potential benefit of the treatment. A 67-year-old male who was initially diagnosed of EGFR L858R-mediated NSCLC received multiple lines of chemotherapy and EGFR TKI therapies after surgery. The EGFR mutational status of individual metastatic lesion was determined by genetic testing of the tumor tissue biopsies using next generation sequencing (NGS) throughout the patient's clinical course. An acquired potentially drug-resistant EGFR mutation was functionally validated in vitro and its sensitivity to different EGFR TKIs was assessed simultaneously. We have identified distinct resistance mechanisms to EGFR blockade in different metastatic lung lesions. Acquired EGFR T790M was first detected that leads to the resistance to the gefitinib treatment. Consequently, osimertinib was administrated and the response lasted until disease progressed. We identified a newly acquired EGFR L718V mutation in one lesion in conjunction with L858R, but not T790M, which showed stable disease on the following erlotinib treatment, while EGFR C797S together with L858R/T790M was detected in the other lesion that continuously progressed. In vitro functional studies demonstrated that EGFR-L858R/L718V confers resistance to osimertinib, but retains sensitivity to the second generation TKI afatinib. We reported that distinct resistance mechanisms could arise in different metastases within the same patient in response to EGFR blockade. We also demonstrated in vitro that EGFR L718V mutation mediates resistance to osimertinib, but retains sensitivity to afatinib. We evidenced that dynamic companion genomic

Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas

2014-06-01

Purpose/Objectives: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), andmore » 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). Conclusions: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system

Successful rechallenge with reduced dose of erlotinib in a patient with lung adenocarcinoma who developed erlotinib-associated leukocytoclastic vasculitis: A case report

PubMed Central

SU, BO-AN; SHEN, WAN-LIN; CHANG, SHENG-TSUNG; FENG, LI-YIA; WU, CHIA-JUNG; FENG, YIN-HSUN

2012-01-01

The oral tyrosine kinase inhibitors of epidermal growth factor, erlotinib and gefitinib, are active in the treatment of non-small cell lung cancer (NSCLC). However, a number of skin manifestations have been found in patients receiving erlotinib therapy. Leukocytoclastic vasculitis is a rare side-effect of erlotinib therapy. However, whether or not erlotinib treatment should be continued when disseminated ulceration of leukocytoclastic vasculitis is encountered remains to be determined. In this study, we report a patient with NSCLC who remains responsive to erlotinib treatment following successful rechallenge with a reduced dose of erlonitib after presenting with severe degree of leukoclastic vasculitis. PMID:22783433

The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.

PubMed

Meany, Holly J; Fox, Elizabeth; McCully, Cynthia; Tucker, Chris; Balis, Frank M

2008-08-01

Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated. Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

The role of BIM-EL and BCL2-α on the efficacy of erlotinib and gefitinib in lung cancer.

PubMed

Simasi, Jacinta; Oelkrug, Christopher; Schubert, Andreas; Nieber, Karen; Gillissen, Adrian

2015-04-01

Tyrosine kinase inhibitors (TKI), erlotinib and gefitinib are small molecule inhibitors which are used for the treatment of lung cancer. But, the development of drug resistance has been reported as one of the major setbacks in oncology. This study focused on the mechanisms leading to secondary resistance by assessing the gene expression of BCL2 family proteins which are associated with the intrinsic apoptotic signaling pathway. 8 genes were investigated in erlotinib and gefitinib treated cells by real time PCR and protein analysis by western blotting. The cells were exposed to the test drugs 48h prior to RNA or protein isolation. It was observed that BIM-EL, a pro-apoptotic protein was up-regulated in cells sensitive to the drugs but not in the resistant cells. On the other hand BCL2-α, an anti-apoptotic protein was up-regulated in the resistant cells and not in the sensitive cells. BCL2-α revealed a counter-regulation effect on BIM-EL and this effect is probably one of the causes of secondary resistance to erlotinib and gefitinib. Copyright © 2014 Elsevier B.V. All rights reserved.

Erlotinib promotes endoplasmic reticulum stress-mediated injury in the intestinal epithelium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fan, Lu; Hu, Lingna; Yang, Baofang

Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down-regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il-6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependently induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib.more » Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients. - Highlights: • Erlotinib destroyed barrier integrity both in vitro and in vivo. • Erlotinib induced inflammation both in vitro and in vivo. • Erlotinib induced apoptosis both in vitro and in vivo. • ER stress contributed to erlotinib-induced barrier dysfunction.« less

Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging.

PubMed

Nishimura, Meiko; Hayashi, Mitsuhiro; Mizutani, Yu; Takenaka, Kei; Imamura, Yoshinori; Chayahara, Naoko; Toyoda, Masanori; Kiyota, Naomi; Mukohara, Toru; Aikawa, Hiroaki; Fujiwara, Yasuhiro; Hamada, Akinobu; Minami, Hironobu

2018-04-06

The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm 2 ; P = 0.009 in paired t -test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm 3 ; P = 0.028 in paired t -test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with laser microdissection.

Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging

PubMed Central

Mizutani, Yu; Takenaka, Kei; Imamura, Yoshinori; Chayahara, Naoko; Toyoda, Masanori; Kiyota, Naomi; Mukohara, Toru; Aikawa, Hiroaki; Fujiwara, Yasuhiro; Hamada, Akinobu; Minami, Hironobu

2018-01-01

Background The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Results Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm2; P = 0.009 in paired t-test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm3; P = 0.028 in paired t-test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Conclusions Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. Methods We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with laser microdissection. PMID:29719624

Erlotinib induced target-like purpura.

PubMed

Rungtrakulchai, R; Rerknimitr, P

2014-02-18

Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor, used as a treatment for advanced stage cancer. The most common side effect is cutaneous toxicity including the already known papulopustular reaction. We herein report a case of erlotinib induced target-like purpura, a peculiar cutaneous adverse event. A 57-year-old patient with advanced non-small cell lung cancer was treated by erolotinib 150 mg daily. After taking the drug for three days, an unusual target-like purpura developed on her lower legs. Skin biopsy specimen taken from the lesion revealed an extravasation of erythrocytes in the upper dermis without destruction of blood vessel walls. This skin eruption cleared after the drug was withdrawn and recurred after erlotinib was re-challenged. The mechanism underlying this cutaneous adverse event remains to be elucidated. Physicians should be aware of the rare side effect of this increasingly used drug.

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

PubMed

Ahn, Peter H; Machtay, Mitchell; Anne, Pramila R; Cognetti, David; Keane, William M; Wuthrick, Evan; Dicker, Adam P; Axelrod, Rita S

2018-05-01

Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

PubMed Central

2012-01-01

Background The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib. PMID:23234355

Molecular Imaging of ABCB1 and ABCG2 Inhibition at the Human Blood-Brain Barrier Using Elacridar and 11C-Erlotinib PET.

PubMed

Verheijen, Remy B; Yaqub, Maqsood; Sawicki, Emilia; van Tellingen, Olaf; Lammertsma, Adriaan A; Nuijen, Bastiaan; Schellens, Jan H M; Beijnen, Jos H; Huitema, Alwin D R; Hendrikse, N Harry; Steeghs, Neeltje

2018-06-01

Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor elacridar on brain uptake using 11 C-erlotinib PET. Methods: Elacridar and cold erlotinib were administered orally to wild-type (WT) and Abcb1a/b;Abcg2 knockout mice. In addition, brain uptake was measured using 11 C-erlotinib imaging and ex vivo scintillation counting in knockout and WT mice. Six patients with advanced solid tumors underwent 11 C-erlotinib PET scans before and after a 1,000-mg dose of elacridar. 11 C-erlotinib brain uptake was quantified by pharmacokinetic modeling using volume of distribution (V T ) as the outcome parameter. In addition, 15 O-H 2 O scans to measure cerebral blood flow were acquired before each 11 C-erlotinib scan. Results: Brain uptake of 11 C-erlotinib was 2.6-fold higher in Abcb1a/b;Abcg2 knockout mice than in WT mice, measured as percentage injected dose per gram of tissue ( P = 0.01). In WT mice, the addition of elacridar (at systemic plasma concentrations of ≥200 ng/mL) resulted in an increased brain concentration of erlotinib, without affecting erlotinib plasma concentration. In patients, the V T of 11 C-erlotinib did not increase after intake of elacridar (0.213 ± 0.12 vs. 0.205 ± 0.07, P = 0.91). 15 O-H 2 O PET showed no significant changes in cerebral blood flow. Elacridar exposure in patients was 401 ± 154 ng/mL. No increase in V T with increased elacridar plasma exposure was found over the 271-619 ng/mL range. Conclusion: When Abcb1 and Abcg2 were disrupted in mice, brain uptake of 11 C-erlotinib increased both at a tracer dose and at a pharmacologic dose. In patients, brain uptake of 11 C-erlotinib was not higher after administration of elacridar. The more pronounced role that ABCG2 appears to play at the human blood-brain barrier and the lower potency of elacridar

Exogenous Restoration of TUSC2 Expression Induces Responsiveness to Erlotinib in Wildtype Epidermal Growth Factor Receptor (EGFR) Lung Cancer Cells through Context Specific Pathways Resulting in Enhanced Therapeutic Efficacy

PubMed Central

Lara-Guerra, Humberto; Kawashima, Hiroyuki; Sakai, Ryo; Jayachandran, Gitanjali; Majidi, Mourad; Mehran, Reza; Wang, Jing; Bekele, B. Nebiyou; Baladandayuthapani, Veerabhadran; Yoo, Suk-Young; Wang, Ying; Ying, Jun; Meng, Feng; Ji, Lin; Roth, Jack A.

2015-01-01

Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR. PMID:26053020

Erlotinib augmentation with dapsone for rash mitigation and increased anti-cancer effectiveness.

PubMed

Kast, R E

2015-01-01

The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib has failed in many ways to be as potent in the anti-cancer role as pre-clinical studies would have suggested. This paper traces some aspects of this failure to a compensatory erlotinib-mediated increase in interleukin-8. Many other-but not all- cancer chemotherapeutic cytotoxic drugs also provoke a compensatory increase in a malignant clone's interleukin-8 synthesis. Untreated glioblastoma and other cancer cells themselves natively synthesize interleukin-8. Interleukin-8 has tumor growth promoting, mobility and metastasis formation enhancing, effects as well as pro-angiogenesis effects. The old sulfone antibiotic dapsone- one of the very first antibiotics in clinical use- has demonstrated several interleukin-8 system inhibiting actions. Review of these indicates dapsone has potential to augment erlotinib effectiveness. Erlotinib typically gives a rash that has recently been proven to come about via an erlotinib triggered up-regulated keratinocyte interleukin-8 synthesis. The erlotinib rash shares histological features reminiscent of typical neutrophilic dermatoses. Dapsone has an established therapeutic role in current treatment of other neutrophilic dermatoses. Thus, dapsone has potential to both improve the quality of life in erlotinib treated patients by amelioration of rash as well as to short-circuit a growth-enhancing aspect of erlotinib when used in the anti-cancer role.

Radiation recall gastritis secondary to erlotinib in a patient with pancreatic cancer.

PubMed

Graziani, Casey; Hegde, Sanjay; Saif, Muhammad Wasif

2014-12-01

Radiation recall refers to chemotherapy-triggered inflammation in healthy areas previously exposed to irradiation. Chemotherapeutics known to be associated with radiation recall phenomenon include anthracyclines, taxanes and antimetabolites, such as gemcitabine and capecitabine. Case reports detailing radiation recall dermatitis and pneumonitis associated with erlotinib have been previously described in the literature, however, there are no reported cases describing radiation gastritis associated with erlotinib. We report a patient with pancreatic cancer who developed gastrointestinal bleeding secondary to radiation recall gastritis related to erlotinib exposure. A 57-year-old Hispanic male with pancreatic cancer initially received 7 cycles of FOLFIRINOX followed by capecitabine with radiation therapy for 28 fractions for a total of 5,040 cGy. Re-staging with computed tomography demonstrated stable disease. The patient was then treated with erlotinib and capecitabine for approximately two months before restaging demonstrated progressive disease. Shortly after discontinuing erlotinib and capecitabine, the patient reported maroon colored stools. Laboratory studies demonstrated a precipitous drop in hemoglobin and hematocrit from pre-treatment baseline, ultimately requiring transfusion with packed red blood cells. Subsequent esophagogastroduodenoscopy demonstrated findings consistent with radiation gastritis, with oozing in the gastric body and antrum, which was treated therapeutically with argon plasma coagulation. The patient's gastrointestinal bleed was difficult to control. Over the course of a two-month period - the patient required multiple admissions, repeat therapeutic esophagogastroduodenoscopies and transfusions. Radiation recall from erlotinib is rare but can potentially arise in any site that has been previously irradiated. There may be an association between the pathogenesis of radiation recall and erlotinib's up-regulation of the angiogenic growth factor

Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420.

PubMed

Broniscer, Alberto; Panetta, John C; O'Shaughnessy, Melinda; Fraga, Charles; Bai, Feng; Krasin, Matthew J; Gajjar, Amar; Stewart, Clinton F

2007-03-01

To report cerebrospinal fluid (CSF) penetration of erlotinib and its metabolite OSI-420. Pharmacokinetic measurements were done in plasma (days 1, 2, 3, and 8 of therapy) and, concurrently, in plasma and CSF (before and at 1, 2, 4, 8, and 24 h after dose on day 34 of therapy) in an 8-year-old patient diagnosed with glioblastoma who received local irradiation and oral erlotinib in a phase I protocol. CSF samples were collected from a ventriculoperitoneal shunt, which was externalized because of infection. Erlotinib concentrations were determined by liquid chromatography/mass spectrometry. CSF penetration of erlotinib and OSI-420 were estimated by a compartmental model and by calculating the ratio of CSF to plasma 24-h area under concentration-time curve (AUC(0-24)). This patient was assigned to receive erlotinib at a dose level of 70 mg/m(2), but the actual daily dose was 75 mg (78 mg/m(2)). Erlotinib and OSI-420 plasma pharmacokinetic variables on days 8 and 34 overlapped to suggest that steady state had been reached. Whereas erlotinib and OSI-420 AUC(0-24) in plasma on day 34 were 30,365 and 2,527 ng h/mL, respectively, the correspondent AUC(0-24) in the CSF were 2,129 and 240 ng h/mL, respectively. Erlotinib and OSI-420 CSF penetration were 7% and approximately 9%, respectively, using both estimate methods. The maximum steady-state CSF concentration of erlotinib was approximately 130 ng/mL (325 nmol/L). The plasma pharmacokinetics of erlotinib in this child overlapped with results described in adults. Oral administration of erlotinib achieves CSF concentrations comparable with those active against several cancer cell lines in preclinical models.

Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature.

PubMed

Singh, Navneet; Jindal, Aditya; Behera, Digambar

2014-12-10

Erlotinib and gefitinib are among the most widely researched, used and available molecularly targeted therapies for treatment of advanced non-small cell lung cancer (NSCLC). They are both tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). In the past decade, there have been reports on clinical benefit from use of erlotinib after gefitinib failure in NSCLC patients. A review of published literature on this focussed topic is provided herein. Pooled analysis of published literature shows that majority of patients were female (60.6%), non-smokers (64.5%), had adenocarcinoma histology (88.3%) and were of East Asian ethnicity (92.3%). Presence of sensitizing EGFR mutation was detected in 48.4% of subjects. Disease control rates with prior gefitinib therapy and with subsequent erlotinib treatment were 79.4% and 45.4% respectively. Based upon our review, the most important predictive factor for clinical benefit from erlotinib identified was previous response to gefitinib. The exact explanations for the potential benefit from erlotinib use in this patient population is still not known and further studies are required to determine the role of molecular mechanisms especially those related to resistance to initial EGFR TKI therapy.

Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine.

PubMed

Kletzl, Heidemarie; Giraudon, Mylene; Ducray, Patricia Sanwald; Abt, Markus; Hamilton, Marta; Lum, Bert L

2015-06-01

The aim of this study was to evaluate the effect of coadministration of acid-reducing agents on the pharmacokinetic exposure of orally administered epidermal growth factor receptor inhibitor erlotinib, a drug that displays pH-dependent solubility. Two studies were conducted, the first with the proton pump inhibitor omeprazole and the second with the H2-receptor antagonist ranitidine. Twenty-four healthy male and female volunteers were enrolled in each study. Erlotinib was administered as a single oral 150 mg dose on day 1. After the washout a subsequent study period evaluated 150 mg erlotinib administered with the acid-reducing agent. Omeprazole (40 mg once daily) was given on days 11-14, concomitantly with erlotinib on day 15, and for two additional days (days 16-17). In the ranitidine study, on day 13, participants were randomized to either concomitant dosing (treatment B) or staggered administration (treatment C) of erlotinib and ranitidine and crossed over to the other treatment starting on day 27. For treatment B, ranitidine (300 mg once daily) was administered in the morning for 5 days, 2 h before erlotinib. For treatment C, ranitidine was administered as a divided dose (150 mg twice daily) for 5 days, with erlotinib given 10 h after the previous evening dose and 2 h before the next ranitidine morning dose. Plasma samples were obtained for determination of the concentrations of erlotinib and its metabolite OSI-420, following each erlotinib dose. All participants were monitored for safety and tolerability. The geometric mean ratios of AUC0-∞ and Cmax for erlotinib and AUC0-last and Cmax for OSI-420 were substantially decreased when erlotinib was dosed with omeprazole. The estimated mean ratio (90% confidence interval) for erlotinib was 0.54 (0.49-0.59) for AUC0-∞ and 0.39 (0.32-0.48) for Cmax. For OSI-420, the estimated mean ratio was 0.42 (0.37-0.48) for AUC0-last and 0.31 (0.24-0.41) for Cmax. AUC0-∞ and Cmax for erlotinib were substantially decreased

Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice.

PubMed

Karbownik, Agnieszka; Szałek, Edyta; Sobańska, Katarzyna; Grabowski, Tomasz; Wolc, Anna; Grześkowiak, Edmund

2017-05-01

Erlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. The rabbits were divided into three groups: the rabbits receiving erlotinib (I ER ), the group receiving paracetamol (II PR ), and the rabbits receiving erlotinib+paracetamol (III ER+PR ). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites - glucuronide and sulphate were measured with the validated method. During paracetamol co-administration we observed increased erlotinib maximum concentration (C max ) and area under the plasma concentration-time curve from time zero to infinity (AUC 0-∞ ) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC 0-∞ by 35.5% and C max by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for C max were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for C max and AUC 0-∞ were 37.1% and 57.1% lower in the II PR group, when compared to the III ER+PR group. Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed. Copyright © 2017. Published by Elsevier B.V.

A case of new onset keratosis pilaris after discontinuation of erlotinib.

PubMed

Okereke, Uchenna R; Colozza, Sara; Cohen, David E

2014-11-01

Keratosis pilaris and keratosis pilaris-like eruptions have been reported in association with RAF inhibitors sorafenib and vemurafenib. We describe herein what is to our knowledge the first reported case of new onset keratosis pilaris after discontinuation of EGFR inhibitor erlotinib. A 60 year-old female with stage IV lung cancer was treated with erlotinib (100 mg/d). The patient elected to discontinue erlotinib after four years secondary to adverse systemic reactions. However, five months later small, monomorphic, rough, folliculocentric papules with surrounding mild erythema characteristic of keratosis pilaris were noted on upper back and arms. This serves as the first documented case of new onset keratosis pilaris in a patient after discontinuation of erlotinib. We report the present case to show the possible association of keratosis pilaris with not only RAF inhibitors, but also the EGFR inhibitor erlotinib. Further investigation will determine whether this is a class effect with other systemic EGFR inhibitors.

Epidermal Growth Factor Receptor Inhibition with Erlotinib Partially Prevents Cisplatin-Induced Nephrotoxicity in Rats

PubMed Central

Matsumoto, Kei; Shindo-Hirai, Yuki; Kuno, Yoshihiro; Yamamoto, Yasutaka; Suzuki, Taihei; Saito, Tomohiro; Iseri, Ken; Shibata, Takanori

2014-01-01

The effects of blocking the epidermal growth factor receptor (EGFR) in acute kidney injury (AKI) are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP)-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP- nephrotoxicity (CP-N). In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. In vitro, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy. PMID:25390346

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.

PubMed

2003-01-01

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in

Simultaneous Determination of Celecoxib, Erlotinib, and its Metabolite Desmethyl-Erlotinib (OSI-420) in Rat Plasma by Liquid chromatography/Tandem Mass Spectrometry with Positive/Negative Ion-Switching Electrospray Ionisation

PubMed Central

Thappali, Satheeshmanikandan R. S.; Varanasi, Kanthikiran; Veeraraghavan, Sridhar; Arla, Rambabu; Chennupati, Sandhya; Rajamanickam, Madheswaran; Vakkalanka, Swaroop; Khagga, Mukkanti

2012-01-01

A new method for the simultaneous determination of celecoxib, erlotinib, and its active metabolite desmethyl-erlotinib (OSI-420) in rat plasma, by liquid chromatography/tandem mass spectrometry with positive/negative ion-switching electrospray ionization mode, was developed and validated. Protein precipitation with methanol was selected as the method for preparing the samples. The analytes were separated on a reverse-phase C18 column (50mm×4.6mm i.d., 3μ) using methanol: 2 mM ammonium acetate buffer, and pH 4.0 as the mobile phase at a flow rate 0.8 mL/min. Sitagliptin and Efervirenz were used as the internal standards for quantification. The determination was carried out on a Theremo Finnigan Quantam ultra triple-quadrupole mass spectrometer, operated in selected reaction monitoring (SRM) mode using the following transitions monitored simultaneously: positive m/z 394.5→278.1 for erlotinib, m/z 380.3→278.1 for desmethyl erlotinib (OSI-420), and negative m/z −380.1→ −316.3 for celecoxib. The limits of quantification (LOQs) were 1.5 ng/mL for Celecoxib, erlotinib, and OSI-420. Within- and between-day accuracy and precision of the validated method were within the acceptable limits of < 15% at all concentrations. The quantitation method was successfully applied for the simultaneous estimation of celecoxib, erlotinib, and desmethyl erlotinib in a pharmacokinetic study in Wistar rats. PMID:23008811

Stability of extemporaneous erlotinib, lapatinib, and imatinib oral suspensions.

PubMed

Li, Quan; Liu, Zhaoying; Kolli, Shamalatha; Wetz, Karen; Griffith, Niesha; Poi, Ming J

2016-09-01

The stability of extemporaneously prepared erlotinib, lapatinib, and imatinib oral liquid dosage forms using two commercially available vehicles when stored at 4 and 25 °C was evaluated. Three batches of extemporaneous oral suspensions were prepared for each drug. Erlotinib and lapatinib tablets were crushed and mixed in a 1:1 mixture of Ora-Plus:Ora-Sweet solution to yield 10- and 50-mg/mL suspensions, respectively. Imatinib tablets were crushed and mixed in Ora-Sweet solution to yield a 40-mg/mL suspension. Suspensions were stored in amber plastic bottles, and samples from each bottle were obtained on days 0, 1, 3, 7, 14, and 28. Erlotinib 10-mg/mL and lapatinib 50-mg/mL oral suspensions in a 1:1 mixture of Ora-Plus and Ora-Sweet retained at least 90% of their initial concentration throughout the 28-day study when stored at 25 °C. Visual inspection revealed notable viscosity changes in the erlotinib and lapatinib suspensions stored at 4 °C for 7 days and beyond. The viscosity of these preparations increased with time and was particularly evident with the erlotinib suspension, which exhibited a puddinglike texture. Imatinib 40-mg/mL oral suspension in Ora-Sweet appeared stable for up to 14 days when stored at both 25 and 4 °C. Erlotinib 10-mg/mL and lapatinib 50-mg/mL oral suspensions prepared from commercially available tablets were stable for at least 28 days when prepared in a 1:1 mixture of Ora-Plus:Ora-Sweet at 25 °C. Imatinib 40-mg/mL oral suspension prepared from commercially available tablets was stable for up to 14 days when prepared in Ora-Sweet and stored at 25 and 4 °C. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second- or third-line treatment of patients with EGFR wild-type advanced non-small cell lung cancer (ECOG-ACRIN 1512): a phase 2 randomised controlled trial

PubMed Central

Neal, Joel W.; Dahlberg, Suzanne E.; Wakelee, Heather A.; Aisner, Seena C.; Bowden, Michaela; Huang, Ying; Carbone, David P.; Gerstner, Gregory J.; Lerner, Rachel E.; Rubin, Jerome L.; Owonikoko, Taofeek K.; Stella, Philip J.; Steen, Preston D.; Khalid, Ahmed Ali; Ramalingam, Suresh S.

2016-01-01

Summary Background Erlotinib is approved for the treatment of all patients with advanced non-small cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We tested the efficacy of cabozantinib and the combination of erlotinib plus cabozantinib, as compared with erlotinib, in patients with EGFR wild-type NSCLC. Methods In this three arm, randomised phase 2 study, the primary endpoint was to compare progression-free survival (PFS) of patients treated with cabozantinib versus erlotinib alone, and the combination of erlotinib plus cabozantinib versus erlotinib alone. Patients were eligible if they had received 1–2 previous treatments for advanced non-squamous EGFR wild-type NSCLC. Patients were stratified by performance status and line of therapy, then randomised using permuted blocks within strata to receive open label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was performed every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single agent arm to receive combination therapy. The comparison between erlotinib and each of the arms was powered (91%) to detect a PFS hazard ratio (HR) of 0.5 (1-sided p-value 0.10-level). Secondary objectives were overall survival (OS), radiographic response by RECIST version 1.1 and description of adverse events by CTCAE version 4.0. This trial is registered with ClinicalTrials.gov, number NCT01708954. Findings At complete enrollment, we randomised 125 patients (42 assigned to erlotinib, 40 assigned to cabozantinib, 43 assigned to the combination), of which 111 (89%) were eligible and received treatment per protocol were included in the primary analysis (38, 38, and 35 patients on erlotinib, cabozantinib, and combination, respectively

Erlotinib: a pharmacoeconomic review of its use in advanced non-small cell lung cancer.

PubMed

Lyseng-Williamson, Katherine A

2010-01-01

Erlotinib (Tarceva), an oral epidermal growth factor receptor tyrosine kinase inhibitor, is associated with modest improvements in survival in patients with advanced non-small cell lung cancer (NSCLC) who have previously received one or more prior chemotherapy regimens. In a well designed clinical trial in this patient population, median overall survival and progression-free survival were significantly longer in patients receiving erlotinib 150 mg/day than in those receiving placebo. Erlotinib is generally well tolerated, with most adverse events being of mild to moderate severity. A large body of modelled pharmacoeconomic data suggests that second- or third-line erlotinib 150 mg/day is a cost-saving option relative to treatment with the approved second-line intravenous chemotherapies of docetaxel and pemetrexed in patients with advanced NSCLC. In patients who had received at least one prior chemotherapy regimen, erlotinib was predicted to be dominant (i.e. more effective and less costly) or cost saving (i.e. equally effective and less costly) relative to docetaxel or pemetrexed with regard to the cost per QALY or life-year gained in cost-effectiveness analyses. Although the effect of erlotinib on overall survival was generally assumed to be equivalent to that of the chemotherapies, the estimated amount of QALYs gained was slightly greater with erlotinib than with docetaxel. In cost-minimization and national budgetary impact analyses, estimated total direct costs with erlotinib were lower than those with docetaxel and pemetrexed, because of the generally lower drug acquisition, administration and adverse event management costs associated with erlotinib. Cost advantages with erlotinib were predicted across analyses, regardless of the type of model developed, specific costs that were included, country that the study was conducted in and year of costing. Sensitivity analyses consistently showed that these results were robust to plausible changes in the key model

Properties of resistant cells generated from lung cancer cell lines treated with EGFR inhibitors.

PubMed

Ghosh, Gargi; Lian, Xiaojun; Kron, Stephen J; Palecek, Sean P

2012-03-20

Epidermal growth factor receptor (EGFR) signaling plays an important role in non-small cell lung cancer (NSCLC) and therapeutics targeted against EGFR have been effective in treating a subset of patients bearing somatic EFGR mutations. However, the cancer eventually progresses during treatment with EGFR inhibitors, even in the patients who respond to these drugs initially. Recent studies have identified that the acquisition of resistance in approximately 50% of cases is due to generation of a secondary mutation (T790M) in the EGFR kinase domain. In about 20% of the cases, resistance is associated with the amplification of MET kinase. In the remaining 30-40% of the cases, the mechanism underpinning the therapeutic resistance is unknown. An erlotinib resistant subline (H1650-ER1) was generated upon continuous exposure of NSCLC cell line NCI-H1650 to erlotinib. Cancer stem cell like traits including expression of stem cell markers, enhanced ability to self-renew and differentiate, and increased tumorigenicity in vitro were assessed in erlotinib resistant H1650-ER1 cells. The erlotinib resistant subline contained a population of cells with properties similar to cancer stem cells. These cells were found to be less sensitive towards erlotinib treatment as measured by cell proliferation and generation of tumor spheres in the presence of erlotinib. Our findings suggest that in cases of NSCLC accompanied by mutant EGFR, treatment targeting inhibition of EGFR kinase activity in differentiated cancer cells may generate a population of cancer cells with stem cell properties.

A Simple High-Performance Liquid Chromatography for Determining Lapatinib and Erlotinib in Human Plasma.

PubMed

Ohgami, Masahiro; Homma, Masato; Suzuki, Yoshiharu; Naito, Kanako; Yamada, Motoko; Mitsuhashi, Shoichi; Fujisawa, Fumie; Kojima, Hiroshi; Kaburagi, Takayuki; Uchiumi, Keiko; Yamada, Yutaka; Bando, Hiroko; Hara, Hisato; Takei, Keiji

2016-12-01

Lapatinib and erlotinib are used for cancer treatment, showing large interindividual variability. Therapeutic drug monitoring may be useful for assessing the clinical outcomes and adverse events. A simple high-performance liquid chromatography UV method was developed for the determination of lapatinib and erlotinib in human plasma. An aliquot of plasma sample spiked with internal standard was treated with acetonitrile to precipitate the proteins. Lapatinib and erlotinib were separated on an octadecylsilyl silica gel column using a mobile phase consisting of acetonitrile, methanol, water, and trifluoroacetic acid (26:26:48:0.1) pumped at a flow rate of 1.0 mL/min. The detection wavelength was set at 316 nm. The calibration curves for lapatinib and erlotinib were linear (r = 0.9999) in the range of 0.125-8.00 mcg/mL. The extraction recoveries for both lapatinib and erlotinib at the plasma concentration of 0.125-8.00 mcg/mL were higher than 89.9% with coefficients of variation less than 3.5%. The coefficients of variation for intraday and interday assays of lapatinib and erlotinib were less than 5.1% and 6.1%, respectively. The present method can be used for blood concentration monitoring for lapatinib or erlotinib in exactly the same conditions.

Pemetrexed-Erlotinib, Pemetrexed Alone, or Erlotinib Alone as Second-Line Treatment for East Asian and Non-East Asian Never-Smokers with Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer: Exploratory Subgroup Analysis of a Phase II Trial

PubMed Central

Lee, Dae Ho; Lee, Jung Shin; Wang, Jie; Hsia, Te-Chun; Wang, Xin; Kim, Jongseok; Orlando, Mauro

2015-01-01

Purpose This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC). Materials and Methods Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model. Results Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months). Conclusion The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients. PMID:25672577

Bovine serum albumin binding study to erlotinib using surface plasmon resonance and molecular docking methods.

PubMed

Taghipour, Parvin; Zakariazadeh, Mostafa; Sharifi, Maryam; Ezzati Nazhad Dolatabadi, Jafar; Barzegar, Abolfazl

2018-06-01

Bovine serum albumin (BSA) is the most abundant protein in the blood circulation and it is commonly used for drug delivery in blood. Therefore, we aim to study BSA interaction with erlotinib as an anticancer drug using surface plasmon resonance (SPR) and molecular modeling methods under physiological conditions (pH = 7.4). BSA immobilized on carboxymethyl dextran hydrogel Au chip (CMD) after activation with N-hydroxysuccinimide and N-ethyl-N-(3-diethylaminopropyl) carbodiimide and then the erlotinib binding to BSA at different concentrations was evaluated. Increasing of erlotinib concentration led to dose-response sensorgrams of BSA. The amount of equilibrium constant (K D ) at 25 °C (4.25 × 10 -9 ) showed the high affinity of erlotinib to BSA. Thermodynamic parameters were attained at four different temperatures. The positive value of enthalpy and entropy showed that hydrophobic forces play major role in the interaction of erlotinib with BSA. Besides, the positive value of Gibbs free energy demonstrated that the interaction of erlotinib with BSA was nonspontaneous and enthalpy driven and the complexion of drug were dependent on endothermic process. According to the molecular docking study, the most favorable binding sites of erlotinib on the BSA were subdomain IIIA and IB. Moreover, molecular docking study results showed that hydrogen binding has a role in intermolecular force that stabilize erlotinib-BSA complex. Copyright © 2018 Elsevier B.V. All rights reserved.

Erlotinib-loaded albumin nanoparticles: A novel injectable form of erlotinib and its in vivo efficacy against pancreatic adenocarcinoma ASPC-1 and PANC-1 cell lines.

PubMed

Noorani, M; Azarpira, N; Karimian, K; Heli, H

2017-10-05

Erlotinib was loaded on albumin nanoparticles for the first time and the cytotoxic effect of the resulting nanoparticles against ASPC-1 and PANC-1 pancreatic adenocarcinoma cell lines was evaluated. The carrier (albumin nanoparticles, ANPs) was synthesized by desolvation method using a mixed solvent followed by thermal crosslinking for stabilization. ANPs and the drug-loaded ANPs were characterized by field emission scanning and transmission electron microscopies, particle size analysis and Fourier transform infrared spectroscopy. The nanoformulation had a size of <14nm with a good monodispersity. Drug loading and encapsulation efficiencies were evaluated as 27 and 44%. Cytotoxicity assays after 72h revealed the potential of ANPs to improve erlotinib toxicity (54% against 34% of free drug toward ASPC-1 cell line, and 52% against 30% toward PANC-1 cell line). Values of IC 50 were obtained for both cell lines and indicated significant reduction in the erlotinib dose necessary for killing the cells, while, ANPs were completely safe. The results demonstrated that erlotinib-loaded ANPs had a remarkable potential for pancreatic cancer drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Economic analysis: randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer.

PubMed

Bradbury, Penelope A; Tu, Dongsheng; Seymour, Lesley; Isogai, Pierre K; Zhu, Liting; Ng, Raymond; Mittmann, Nicole; Tsao, Ming-Sound; Evans, William K; Shepherd, Frances A; Leighl, Natasha B

2010-03-03

The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non-small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer-related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94,638 per life-year gained (95% confidence interval = $52,359 to $429,148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. With an incremental cost-effectiveness ratio of $94 638 per life-year gained, erlotinib treatment for patients with previously treated

Epidermal growth factor receptor inhibition with erlotinib ameliorates anti-Thy 1.1-induced experimental glomerulonephritis.

PubMed

Rintala, Jukka M; Savikko, Johanna; Rintala, Sini E; Palin, Niina; Koskinen, Petri K

2016-06-01

Mesangial proliferative glomerulonephritis is a common glomerular disorder that may lead to end-stage renal disease. Epidermal growth factor (EGF) plays an important role in the regulation of cell growth, proliferation, and differentiation and in the pathology of various renal diseases. Erlotinib is a novel, oral, highly selective tyrosine kinase inhibitor of the EGF receptor. It is clinically used to treat non-small cell lung and pancreatic cancers. Here, we investigated the effect of erlotinib on the progression of mesangioproliferative glomerulonephritis in an experimental model. Mesangial glomerulonephritis was induced with anti-rat Thy-1.1 antibody in male Wistar rats weighing 150-160 g. Rats were treated with erlotinib (10 mg/kg/day p.o.) or vehicle only (polyethylene glycol). Native Wistar rat kidneys were used as histological controls. Serum creatinine levels were measured at day 7. Kidneys were harvested 7 days after antibody administration for histology. Native controls showed no histological signs of glomerular pathology. In the vehicle group, intense glomerular inflammation developed after 7 days and prominent mesangial cell proliferation and glomerular matrix accumulation was seen. Erlotinib was well tolerated and there were no adverse effects during the follow-up period. Erlotinib significantly prevented progression of the glomerular inflammatory response and glomerular mesangial cell proliferation as well as matrix accumulation when compared with the vehicle group. Erlotinib also preserved renal function. These results indicate that erlotinib prevents the early events of experimental mesangial proliferative glomerulonephritis. Therefore, inhibition of the EGF receptor with erlotinib could prevent the progression of glomerulonephritis also in clinical nephrology.

Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in BXPC-3 and PANC-1 human pancreatic cancer cells.

PubMed

Wang, Lin; Zhu, Zhi-Xia; Zhang, Wen-Ying; Zhang, Wei-Min

2011-09-01

Previous studies have shown that both pemetrexed, a cytotoxic drug, and erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), inhibit the cell growth of pancreatic cancer cells. However, whether they exert a synergistic antitumor effect on pancreatic cancer cells remains unknown. The present study aimed to assess the synergistic effect of erlotinib in combination with pemetrexed using different sequential administration schedules on the proliferation of human pancreatic cancer BXPC-3 and PANC-1 cells and to probe its cellular mechanism. The EGFR and K-ras gene mutation status was examined by quantitative PCR high-resolution melting (qPCR-HRM) analysis. BXPC-3 and PANC-1 cells were incubated with pemetrexed and erlotinib using different administration schedules. MTT assay was used to determine cytotoxicity, and cell cycle distribution was determined by flow cytometry. The expression and phosphorylation of EGFR, HER3, AKT and MET were determined using Western blotting. Both pemetrexed and erlotinib inhibited the proliferation of BXPC-3 and PANC-1 cells in a dose- and time-dependent manner in vitro. Synergistic effects on cell proliferation were observed when pemetrexed was used in combination with erlotinib. The degree of the synergistic effects depended on the administration sequence, which was most obvious when erlotinib was sequentially administered at 24-h interval following pemetrexed. Cell cycle studies revealed that pemetrexed induced S arrest and erlotinib induced G(0)/G(1) arrest. The sequential administration of erlotinib following pemetrexed induced S arrest. Western blot analyses showed that pemetrexed increased and erlotinib decreased the phosphorylation of EGFR, HER3 and AKT, respectively. However, both pemetrexed and erlotinib exerted no significant effects on the phosphorylation of c-MET. The phosphorylation of EGFR, HER3 and AKT was significantly suppressed by scheduled incubation with pemetrexed followed by erlotinib

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

PubMed Central

Monsma, David J; Cherba, David M; Eugster, Emily E; Dylewski, Dawna L; Davidson, Paula T; Peterson, Chelsea A; Borgman, Andrew S; Winn, Mary E; Dykema, Karl J; Webb, Craig P; MacKeigan, Jeffrey P; Duesbery, Nicholas S; Nickoloff, Brian J; Monks, Noel R

2015-01-01

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAFV600E models showed acquired drug resistance, one BRAFV600E model had a complete and durable response, and a BRAFV600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations. PMID:26101714

A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance.

PubMed

Lee, Hee Seung; Park, Soo Been; Kim, Sun A; Kwon, Sool Ki; Cha, Hyunju; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Song, Si Young

2017-01-30

Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future.

A novel HDAC inhibitor, CG200745, inhibits pancreatic cancer cell growth and overcomes gemcitabine resistance

PubMed Central

Lee, Hee Seung; Park, Soo Been; Kim, Sun A; Kwon, Sool Ki; Cha, Hyunju; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Song, Si Young

2017-01-01

Pancreatic cancer is predominantly lethal, and is primarily treated using gemcitabine, with increasing resistance. Therefore, novel agents that increase tumor sensitivity to gemcitabine are needed. Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents, since HDAC plays an important role in cancer initiation and progression. We evaluated the antitumor effect of a novel HDAC inhibitor, CG200745, combined with gemcitabine/erlotinib on pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells. Three pancreatic cancer-cell lines were used to evaluate the antitumor effect of CG200745 combined with gemcitabine/erlotinib. CG200745 induced the expression of apoptotic proteins (PARP and caspase-3) and increased the levels of acetylated histone H3. CG200745 with gemcitabine/erlotinib showed significant growth inhibition and synergistic antitumor effects in vitro. In vivo, gemcitabine/erlotinib and CG200745 reduced tumor size up to 50%. CG200745 enhanced the sensitivity of gemcitabine-resistant pancreatic cancer cells to gemcitabine, and decreased the level of ATP-binding cassette-transporter genes, especially multidrug resistance protein 3 (MRP3) and MRP4. The novel HDAC inhibitor, CG200745, with gemcitabine/erlotinib had a synergistic anti-tumor effect on pancreatic cancer cells. CG200745 significantly improved pancreatic cancer sensitivity to gemcitabine, with a prominent antitumor effect on gemcitabine-resistant pancreatic cancer cells. Therefore, improved clinical outcome is expected in the future. PMID:28134290

NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sobhakumari, Arya; Department of Pathology, The University of Iowa, Iowa City, IA; Schickling, Brandon M.

2013-11-01

Most head and neck squamous cell carcinomas (HNSCCs) overexpress epidermal growth factor receptor (EGFR) and EGFR inhibitors are routinely used in the treatment of HNSCC. However, many HNSCC tumors do not respond or become refractory to EGFR inhibitors. Autophagy, which is a stress-induced cellular self-degradation process, has been reported to reduce the efficacy of chemotherapy in various disease models. The purpose of this study is to determine if the efficacy of the EGFR inhibitor erlotinib is reduced by activation of autophagy via NOX4-mediated oxidative stress in HNSCC cells. Erlotinib induced the expression of the autophagy marker LC3B-II and autophagosome formationmore » in FaDu and Cal-27 cells. Inhibition of autophagy by chloroquine and knockdown of autophagy pathway genes Beclin-1 and Atg5 sensitized both cell lines to erlotinib-induced cytotoxicity, suggesting that autophagy may serve as a protective mechanism. Treatment with catalase (CAT) and diphenylene iodonium (DPI) in the presence of erlotinib suppressed the increase in LC3B-II expression in FaDu and Cal-27 cells. Erlotinib increased NOX4 mRNA and protein expression by increasing its promoter activity and mRNA stability in FaDu cells. Knockdown of NOX4 using adenoviral siNOX4 partially suppressed erlotinib-induced LC3B-II expression, while overexpression of NOX4 increased expression of LC3B-II. These studies suggest that erlotinib may activate autophagy in HNSCC cells as a pro-survival mechanism, and NOX4 may play a role in mediating this effect. - Highlights: • Erlotinib increased LC3B-II and autophagosome formation in HNSCC cells. • Inhibition of autophagy sensitized HNSCC cells to erlotinib. • Erlotinib increased NOX4 promoter and 3′UTR luciferase activity. • Manipulating NOX4 decreases or increases autophagy.« less

Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro

PubMed Central

Feng, Xiuli; Zhang, Yan; Li, Tao; Li, Yu

2017-01-01

Combination of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved to be a potent anti-drug for the treatment of tumors. However, survival time was not extended for the patients with lung adenocarcinoma (AdC) compared with first-line chemotherapy. In the present study, we attempt to assess the optimal schedule of the combined administration of pemetrexed and icotinib/erlotinib in AdC cell lines. Human lung AdC cell lines with wild-type (A549), EGFR T790M (H1975) and activating EGFR mutation (HCC827) were applied in vitro to assess the differential efficacy of various sequential regimens on cell viability, cell apoptosis and cell cycle distribution. The results suggested that the antiproliferative effect of the sequence of pemetrexed followed by icotinib/erlotinib was more effective than that of icotinib/erlotinib followed by pemetrexed. Additionally, a reduction of G1 phase and increased S phase in sequence of pemetrexed followed by icotinib/erlotinib was also observed, promoting cell apoptosis. Thus, the sequential administration of pemetrexed followed by icotinib/erlotinib exerted a synergistic effect on HCC827 and H1975 cell lines compared with the reverse sequence. The sequential treatment of pemetrexed followed by icotinib/erlotinib has been demonstrated promising results. This treatment strategy warrants further confirmation in patients with advanced lung AdC. PMID:29371987

Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro.

PubMed

Feng, Xiuli; Zhang, Yan; Li, Tao; Li, Yu

2017-12-26

Combination of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved to be a potent anti-drug for the treatment of tumors. However, survival time was not extended for the patients with lung adenocarcinoma (AdC) compared with first-line chemotherapy. In the present study, we attempt to assess the optimal schedule of the combined administration of pemetrexed and icotinib/erlotinib in AdC cell lines. Human lung AdC cell lines with wild-type (A549), EGFR T790M (H1975) and activating EGFR mutation (HCC827) were applied in vitro to assess the differential efficacy of various sequential regimens on cell viability, cell apoptosis and cell cycle distribution. The results suggested that the antiproliferative effect of the sequence of pemetrexed followed by icotinib/erlotinib was more effective than that of icotinib/erlotinib followed by pemetrexed. Additionally, a reduction of G1 phase and increased S phase in sequence of pemetrexed followed by icotinib/erlotinib was also observed, promoting cell apoptosis. Thus, the sequential administration of pemetrexed followed by icotinib/erlotinib exerted a synergistic effect on HCC827 and H1975 cell lines compared with the reverse sequence. The sequential treatment of pemetrexed followed by icotinib/erlotinib has been demonstrated promising results. This treatment strategy warrants further confirmation in patients with advanced lung AdC.

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

PubMed Central

DENG, YANMING; FENG, WEINENG; WU, JING; CHEN, ZECHENG; TANG, YICONG; ZHANG, HUA; LIANG, JIANMIAO; XIAN, HAIBING; ZHANG, SHUNDA

2014-01-01

It has been demonstrated that erlotinib is effective in treating patients with brain metastasis from non-small-cell lung cancer. However, the number of studies determining the erlotinib concentration in these patients is limited. The purpose of this study was to measure the concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung carcinoma. Six patients were treated with the standard recommended daily dose of erlotinib (150 mg) for 4 weeks. All the patients had previously received chemotherapy, but no brain radiotherapy. At the end of the treatment period, blood plasma and cerebrospinal fluid samples were collected and the erlotinib concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The average erlotinib concentration in the blood plasma and the cerebrospinal fluid was 717.7±459.7 and 23.7±13.4 ng/ml, respectively. The blood-brain barrier permeation rate of erlotinib was found to be 4.4±3.2%. In patients with partial response (PR), stable disease (SD) and progressive disease (PD), the average concentrations of erlotinib in the cerebrospinal fluid were 35.5±19.0, 19.1±8.7 and 16.4±5.9 ng/ml, respectively. In addition, the efficacy rate of erlotinib for metastatic brain lesions was 33.3%, increasing to 50% in patients with EGFR mutations. However, erlotinib appeared to be ineffective in cases with wild-type EGFR. In conclusion, a relatively high concentration of erlotinib was detected in the cerebrospinal fluid of patients with brain metastases from non-small-cell lung cancer. Thus, erlotinib may be considered as a treatment option for this patient population. PMID:24649318

Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

PubMed Central

Xia, Jinjing; Bai, Hao; Yan, Bo; Li, Rong; Shao, Minhua; Xiong, Liwen; Han, Baohui

2017-01-01

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12.24%). Median progression-free and overall survival was markedly shorter in patients with BIM deletion polymorphism than with BIM wide-type. Moreover, NSCLC cells expressing EGFR-mutant harboring BIM polymorphism were more resistant to erlotinib-induced apoptosis than BIM wide-type cells. However, combined use of erlotinib and the BH3-mimetic ABT-737 up-regulated BIM expression and overcame erlotinib resistance in EGFR-mutant NSCLC cells harboring BIM deletion polymorphism. In vivo, erlotinib suppressed growth of BIM wide-type NSCLC cell xenographs by inducing apoptosis. Combined with ABT-737, erlotinib also suppressed NSCLC xenographs expressing EGFR-mutant harboring BIM deletion polymorphism. These results indicate that BIM polymorphism is closely related to a poor clinical response to EGFR TKIs in EGFR-mutant NSCLC patients, and that the BH3-mimetic ABT-737 restores BIM functionality and EGFR-TKI sensitivity. PMID:29312548

Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer.

PubMed

Xia, Jinjing; Bai, Hao; Yan, Bo; Li, Rong; Shao, Minhua; Xiong, Liwen; Han, Baohui

2017-12-12

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12.24%). Median progression-free and overall survival was markedly shorter in patients with BIM deletion polymorphism than with BIM wide-type. Moreover, NSCLC cells expressing EGFR-mutant harboring BIM polymorphism were more resistant to erlotinib-induced apoptosis than BIM wide-type cells. However, combined use of erlotinib and the BH3-mimetic ABT-737 up-regulated BIM expression and overcame erlotinib resistance in EGFR-mutant NSCLC cells harboring BIM deletion polymorphism. In vivo , erlotinib suppressed growth of BIM wide-type NSCLC cell xenographs by inducing apoptosis. Combined with ABT-737, erlotinib also suppressed NSCLC xenographs expressing EGFR-mutant harboring BIM deletion polymorphism. These results indicate that BIM polymorphism is closely related to a poor clinical response to EGFR TKIs in EGFR-mutant NSCLC patients, and that the BH3-mimetic ABT-737 restores BIM functionality and EGFR-TKI sensitivity.

Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC.

PubMed

Knebel, Franciele H; Bettoni, Fabiana; Shimada, Andrea K; Cruz, Manoel; Alessi, João Victor; Negrão, Marcelo V; Reis, Luiz Fernando L; Katz, Artur; Camargo, Anamaria A

2017-06-01

Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Sequential liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation. Erlotinib was discontinued and osimertinib was initiated. Blood samples were collected at erlotinib progression and during osimertinib treatment for the detection of the activating (EGFR-exon19del) and resistance mutations (EGFR-T790M, EGFR-C797S, BRAF-V600E, METamp and ERBB2amp) in the plasma DNA using digital droplet PCR. Plasma levels of the activating EGFR-exon19del accurately paralleled the clinical and radiological progression of disease and allowed early detection of AR to osimertinib. Resistance to osimertinib coincided with the emergence of a small tumor cell subpopulation carrying the known EGFR-C797S resistance mutation and an additional subpopulation carrying amplified copies of EGFR-exon19del. Given the existence of multiple AR mechanisms, quantification of the original EGFR activation mutation, instead of the resistance mutations, can be efficiently used to monitor response to osimertinib, allowing early detection of AR. Absolute quantification of both activation and resistance mutations can provide important information on tumor clonal evolution upon progression to osimertinib. Selective amplification of the EGFR-exon19del allele may represent a novel resistance mechanism to osimertinib. Copyright © 2017 Elsevier B.V. All rights reserved.

A Prospective Evaluation of Circulating Tumor Cells and Cell-Free DNA in EGFR-Mutant Non-Small Cell Lung Cancer Patients Treated with Erlotinib on a Phase II Trial.

PubMed

Yanagita, Masahiko; Redig, Amanda J; Paweletz, Cloud P; Dahlberg, Suzanne E; O'Connell, Allison; Feeney, Nora; Taibi, Myriam; Boucher, David; Oxnard, Geoffrey R; Johnson, Bruce E; Costa, Daniel B; Jackman, David M; Jänne, Pasi A

2016-12-15

Genotype-directed therapy is the standard of care for advanced non-small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in EGFR-mutant NSCLC patients treated with erlotinib until progression. EGFR-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for EGFR19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and EGFR and MET FISH were also performed. Rebiopsy was performed at disease progression. Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified MET amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival. cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. Clin Cancer Res; 22(24); 6010-20. ©2016 AACR. ©2016 American Association for Cancer Research.

Efficacy and safety of bevacizumab plus erlotinib versus bevacizumab or erlotinib alone in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis

PubMed Central

Zhang, Shu; Mao, Xiao-dong; Wang, Hai-tao; Cai, Feng; Xu, Jing

2016-01-01

Objectives Bevacizumab and erlotinib inhibit different tumour growth pathways, and both exhibit beneficial effects in the treatment of non-small-cell lung cancer (NSCLC). However, the efficacy of bevacizumab in combination with erlotinib remains controversial. Therefore, we conducted a meta-analysis to compare combination treatment with bevacizumab and erlotinib to bevacizumab or erlotinib monotherapy in the treatment of NSCLC. Methods Randomised controlled trials (RCTs) published in PubMed, Web of Science and EMBASE were systematically reviewed. The main outcome measures included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Results were expressed as HRs or risk ratios (RRs) with 95% CIs. Results 5 RCTs involving a total of 1736 patients were included in this meta-analysis. The combination of bevacizumab and erlotinib significantly improved PFS (HR=0.63, 95% CI 0.53 to 0.75; p=0.000) and the ORR (RR=1.91, 95% CI 1.19 to 3.06; p=0.007) in the second-line treatment of NSCLC compared with bevacizumab or erlotinib alone. However, no significant difference in OS was observed between the combination and monotherapy groups (HR=0.96, 95% CI 0.83 to 1.11; p=0.573). A subgroup analysis has shown that the greatest PFS benefit was associated with an age of <65 years(HR=0.74, 95% CI 0.57 to 0.96; p=0.026), Asian/Pacific Islander ethnicity (HR=0.23, 95% CI 0.10 to 0.54; p=0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) 1 (HR=0.82, 95% CI 0.68 to 0.98; p=0.033), stage IIIB or IV disease (HR=0.68, 95% CI 0.57 to 0.82; p=0.000) and no history of smoking (HR=0.48, 95% CI 0.32 to 0.71; p=0.000). The incidence of grade 3/4 adverse events such as rash and diarrhoea was higher in the combination group than in the monotherapy group. Conclusions The addition of bevacizumab to erlotinib can significantly improve PFS and the ORR in the second-line treatment of NSCLC with an acceptable and manageable risk of

Pilot study of erlotinib in patients with acute myeloid leukemia.

PubMed

Sayar, Hamid; Czader, Magdalena; Amin, Chirag; Cangany, Mary; Konig, Heiko; Cripe, Larry D

2015-02-01

We conducted a pilot study to investigate clinical efficacy of tyrosine kinase inhibitor erlotinib in the treatment of acute myeloid leukemia (AML). A total of 11 patients with de novo AML were treated, including 2 with relapsed and/or refractory disease and 9 older patients with previously untreated AML. Patients with high baseline leukocyte count were excluded. Erlotinib was given orally at 150 mg per day continuously in 28-day cycles. The treatment was tolerated well, and no toxicities were observed. An initial reduction in circulating blasts, followed by disease progression, was observed in 2 patients. Nine other patients did not demonstrate any response in blood or bone marrow. Baseline and post-cycle 1 flow-cytometry were performed on bone marrow blasts to investigate signs of differentiation. No immunophenotypic changes suggestive of differentiation were observed. This pilot study did not demonstrate response to standard doses of erlotinib in patients with AML. Copyright © 2014 Elsevier Ltd. All rights reserved.

Influence of the Acidic Beverage Cola on the Absorption of Erlotinib in Patients With Non-Small-Cell Lung Cancer.

PubMed

van Leeuwen, Roelof W F; Peric, Robert; Hussaarts, Koen G A M; Kienhuis, Emma; IJzerman, Nikki S; de Bruijn, Peter; van der Leest, Cor; Codrington, Henk; Kloover, Jeroen S; van der Holt, Bronno; Aerts, Joachim G; van Gelder, Teun; Mathijssen, Ron H J

2016-04-20

Erlotinib depends on stomach pH for its bioavailability. When erlotinib is taken concurrently with a proton pump inhibitor (PPI), stomach pH increases, which results in a clinically relevant decrease of erlotinib bioavailability. We hypothesized that this drug-drug interaction is reversed by taking erlotinib with the acidic beverage cola. The effects of cola on erlotinib bioavailability in patients not treated with a PPI were also studied. In this randomized, cross-over, pharmacokinetic study in patients with non-small-cell lung cancer, we studied intrapatient differences in absorption (area under the plasma concentration time curve [AUC0-12h]) after a 7-day period of concomitant treatment with erlotinib, with or without esomeprazole, with either cola or water. At the 7th and 14th day, patients were hospitalized for 1 day for pharmacokinetic sampling. Twenty-eight evaluable patients were included in the analysis. In patients treated with erlotinib and esomeprazole with cola, the mean AUC0-12h increased 39% (range, -12% to 136%; P = .004), whereas in patients not treated with the PPI, the mean AUC0-12h was only slightly higher (9%; range, -10% to +30%; P = .03) after erlotinib intake with cola. Cola intake led to a clinically relevant and statistically significant increase in the bioavailability of erlotinib during esomeprazole treatment. In patients not treated with the PPI, the effects of cola were marginal. These findings can be used to optimize the management of drug-drug interactions between PPIs and erlotinib. © 2016 by American Society of Clinical Oncology.

Surveillance for Travel and Domestically Acquired Multidrug-Resistant Human Shigella Infections-Pennsylvania, 2006-2014.

PubMed

Li, Yu Lung; Tewari, Deepanker; Yealy, Courtney C; Fardig, David; M'ikanatha, Nkuchia M

2016-01-01

Shigellosis is a leading cause of enteric infections in the United States. We compared antimicrobial resistance in Shigella infections related to overseas travel (travel-associated) and in those acquired domestically by analyzing antimicrobial resistance patterns, geographic distributions, and pulsed-field gel electrophoresis (PFGE) patterns. We tested samples (n = 204) from a collection of isolates recovered from patients in Pennsylvania between 2006 and 2014. Isolates were grouped into travel- and non-travel-associated categories. Eighty-one (79.4%) of the Shigella isolates acquired during international travel were resistant to multiple antibiotics compared to 53 (52.1%) of the infections transmitted in domestic settings. A majority (79.4%) of isolates associated with international travel demonstrated resistance to aminoglycosides and tetracyclines, whereas 47 (46.1%) of the infections acquired domestically were resistant to tetracycline. Almost all isolates (92.2%) transmitted in domestic settings were resistant to aminoglycosides, and 5 isolates from adult male patients were resistant to azithromycin, a drug often used for empiric treatment of severe shigellosis. Twenty (19.6%) isolates associated with illnesses acquired during overseas travel in 4 countries were resistant to quinolones. One S. sonnei PFGE pattern was traced to a multidrug-resistant isolate acquired overseas that had caused a multistate outbreak of shigellosis, suggesting global dissemination of a drug-resistant species. Resistance to certain drugs-for example, tetracycline-increased in both overseas- and domestic-acquired infections during the study period. The prevalence of resistance to macrolides (azithromycin) and third-generation cephalosporins (ceftriaxone) was less than 1%; however, efforts to better monitor changes in drug resistance over time combined with increased antimicrobial stewardship are essential at the local, national, and global levels.

A Research-Inspired Laboratory Sequence Investigating Acquired Drug Resistance

ERIC Educational Resources Information Center

Taylor, Elizabeth Vogel; Fortune, Jennifer A.; Drennan, Catherine L.

2010-01-01

Here, we present a six-session laboratory exercise designed to introduce students to standard biochemical techniques in the context of investigating a high impact research topic, acquired resistance to the cancer drug Gleevec. Students express a Gleevec-resistant mutant of the Abelson tyrosine kinase domain, the active domain of an oncogenic…

Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

PubMed Central

Wang, Jun; Wang, Baocheng; Chu, Huili; Yao, Yunfeng

2016-01-01

Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Moreover, ~20%–30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance. PMID:27382309

Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer

PubMed Central

Huether, Alexander; Höpfner, Michael; Sutter, Andreas P; Baradari, Viola; Schuppan, Detlef; Scherübl, Hans

2006-01-01

AIM: To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC). METHODS: Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS: Erlotinib treatment inhibited the mitogen activated protein (MAP)-kinase pathway and signal transducer of activation and transcription (STAT)-mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib's potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib’s inhibitory effects on the receptor-receptor cross talk. CONCLUSION: Our study sheds light on the under-standing of the mechanisms of action of EGFR-TK-inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future. PMID:16937526

Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer.

PubMed

Ohgami, Masahiro; Kaburagi, Takayuki; Kurosawa, Atsuhiko; Homma, Masato

2016-11-01

Erlotinib, a substrate drug metabolized by the CYP3A4 enzyme, is an epidermal growth factor receptor tyrosine kinase inhibitor used to treat nonsmall cell lung cancer (NSCLC). Concomitant use of erlotinib and the antiepileptic drug phenytoin, an inducer of CYP3A4, may result in a drug-drug interaction accompanied by changes in the blood concentrations of both drugs. We determined the blood concentration of each drug to confirm the interaction between phenytoin and erlotinib in a case of NSCLC with brain metastases. The phenytoin blood concentration (8.2-10.0μg/mL) gradually increased 3-fold (to 24.2μg/mL) 7 months after the start of erlotinib (150mg/d) co-administration. The erlotinib blood concentration which was maintained at 0.15-0.37μg/mL under phenytoin co-administration, increased 12-fold (to 1.77μg/mL) after the stoppage of phenytoin co-administration. The present case revealed that blood phenytoin increased and blood erlotinib decreased subsequent to the interaction of the 2 drugs in the CYP3A4 metabolic enzyme system. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

ABCB1 as predominant resistance mechanism in cells with acquired SNS-032 resistance

PubMed Central

Rothweiler, Florian; Voges, Yvonne; Balónová, Barbora; Blight, Barry A.; Cinatl, Jindrich

2016-01-01

The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation. PMID:27517323

Synergistic effect between erlotinib and MEK inhibitors in KRAS wildtype human pancreatic cancer cells

PubMed Central

Diep, Caroline H.; Munoz, Ruben M.; Choudhary, Ashish; Von Hoff, Daniel D.; Han, Haiyong

2011-01-01

Purpose The combination of gemcitabine plus erlotinib has shown a small but statistically significant survival advantage when compared to gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study we sought to identify gene targets that, when inhibited, would enhance the activity of EGFR-targeted therapies in pancreatic cancer cells. Experimental Design A high-throughput RNAi screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays. Results Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, MAPK1, was selected for further mechanistic studies. Combination treatments of erlotinib plus two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119-erlotinib and AZD6244-erlotinib) compared to the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wildtype cells but not in KRAS mutant cells. Conclusions Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer. PMID:21385921

Conclusions of the expert panel: importance of erlotinib as a second-line therapeutic option

PubMed Central

Castagnari, Aldo

2008-01-01

During the Experts Meeting on Lung Cancer, participants emphasized the usefulness of erlotinib as second-line therapy for lung cancer. They noted that, although there are no comparative studies, erlotinib could be as effective as docetaxel and pemetrexed in second-line therapy. Regarding the toxicity profile of each of these drugs – one of the key issues considered in the meeting – specialists pointed out how important it is to clearly identify existing differences in this issue. Each drug has different degrees of toxicity, and this information is crucial at the time of choosing the therapeutic regimen. Erlotinib treatment could be an effective option for second-line therapy. PMID:18831720

Handling a community-acquired methicillin-resistant Staphylococcus aureus outbreak: emerging data.

PubMed

Elston, Dirk M

2008-08-01

Community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) strains continue to emerge as important causes of sepsis, folliculitis, skin abscesses, necrotizing pneumonitis, empyema, and bone and joint infections. Community-acquired methicillin-resistant S aureus often affects young, previously healthy individuals, including athletes and children in day care. Drainage remains the most important intervention for an abscess. The most common CAMRSA strains in the United States, Canada, and Europe remain sensitive to sulfonamides and tetracycline. Rates of clindamycin resistance vary widely geographically, and physicians should be familiar with their local antibiogram data. Multidrug-resistant strains of CAMRSA are emerging, and the routine addition of antibiotics such as tetracycline to animal feed is contributing to the emergence of resistance. Recurrence and spread of infection can be reduced by addressing the carrier state. Strategies for treatment and elimination of staphylococcal carriage are discussed.

Community-Acquired Methicillin-Resistant "Staphylococcus aureus": Considerations for School Nurses

ERIC Educational Resources Information Center

Alex, Aniltta; Letizia, MariJo

2007-01-01

Methicillin-resistant "Staphylococcus aureus" (MRSA) is a disease-causing organism that has been present in hospital settings since the 1960s. However, a genetically distinct strain of MRSA, called community-acquired methicillin-resistant "Staphylococcus aureus" (CA-MRSA), has emerged in recent years in community settings among healthy…

Drug Penetration Gradients Associated with Acquired Drug Resistance in Tuberculosis Patients.

PubMed

Dheda, Keertan; Lenders, Laura; Magombedze, Gesham; Srivastava, Shashikant; Raj, Prithvi; Arning, Erland; Ashcraft, Paula; Bottiglieri, Teodoro; Wainwright, Helen; Pennel, Timothy; Linegar, Anthony; Moodley, Loven; Pooran, Anil; Pasipanodya, Jotam G; Sirgel, Frederick A; van Helden, Paul D; Wakeland, Edward; Warren, Robin M; Gumbo, Tawanda

2018-06-07

Acquired resistance is an important driver of multidrug-resistant tuberculosis, even with good treatment adherence. However, exactly what initiates the resistance, and how it arises remains poorly understood. To identify the relationship between drug concentrations and drug susceptibility readouts (MICs) in the tuberculosis cavity. We recruited patients with medically incurable tuberculosis who were undergoing therapeutic lung resection whilst on treatment with the cocktail of second line anti-tuberculosis drugs. On the day of surgery antibiotic concentrations were measured in the blood and at seven pre-specified biopsy sites within each cavity. Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug identified, and whole genome sequencing performed. Spearman correlation coefficients between drug concentration and MIC were calculated. Fourteen patients treated for a median of 13 (range: 5-31) months were recruited. MICs and drug resistance-associated single nucleotide variants differed between the different geospatial locations within each cavity, and with pretreatment and serial sputum isolates, consistent with ongoing acquisition of resistance. However, pre-treatment sputum MIC had an accuracy of only 49.48% in predicting cavitary MICs. There were large concentration-distance gradients for each antibiotic. The location-specific concentrations inversely correlated with MICs (p<0.05), and therefore acquired resistance. Moreover, pharmacokinetic/pharmacodynamic exposures known to amplify drug-resistant subpopulations were encountered in all positions. These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

Oral erlotinib, but not rapamycin, causes modest acceleration of bladder and hindlimb recovery from spinal cord injury in rats.

PubMed

Kjell, J; Pernold, K; Olson, L; Abrams, M B

2014-03-01

Erlotinib and Rapamycin are both in clinical use and experimental inhibition of their respective molecular targets, EGFR and mTORC1, has improved recovery from spinal cord injury. Our aim was to determine if daily Erlotinib or Rapamycin treatment started directly after spinal contusion injury in rats improves locomotion function or recovery of bladder function. Stockholm, Sweden. Rats were subjected to contusion injuries and treated during the acute phase with either Erlotinib or Rapamycin. Recovery of bladder function was monitored by measuring residual urine volume and hindlimb locomotion assessed by open-field observations using the BBB rating scale as well as by automated registration of gait parameters. Body weights were monitored. To determine whether Erlotinib and Rapamycin inhibit the same signaling pathway, a cell culture system and western blots were used. Erlotinib accelerated locomotor recovery and slightly improved bladder recovery; however, we found no long-term improvements of locomotor function. Rapamycin did neither improved locomotor function nor bladder recovery. In vitro studies confirmed that Erlotinib and Rapamycin both inhibit the EGFR-mTORC1 signaling pathway. We conclude that none of these two drug regimes improved long-term functional outcome in our current model of spinal cord injury. Nevertheless, oral treatment with Erlotinib may offer modest temporary advantages, whereas treatment with Rapamycin does not.

The Risk of Neutropenia and Leukopenia in Advanced Non-Small Cell Lung Cancer Patients Treated With Erlotinib

PubMed Central

Zhou, Jian-Guo; Tian, Xu; Cheng, Long; Zhou, Quan; Liu, Yuan; Zhang, Yu; Bai, Yu-ju; Ma, Hu

2015-01-01

Abstract Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a critical member of systemic therapy for advanced non-small-cell lung cancer (NSCLC). Erlotinib is the first-generation EGFR-TKIs, the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations. However, the safety of erlotinib plus chemotherapy (CT) or erlotinib alone for advanced NSCLC remains controversial. We carried out a systematic meta-analysis to determine the overall risk of neutropenia and leukopenia associated with erlotinib. PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. RR with 95% CIs for neutropenia and leukopenia were all extracted. The random-effects model was used to calculate pooled RRs and 95% CIs. Power calculation was performed using macro embedded in SAS software after all syntheses were conducted. We identified 12 eligible studies involving 3932 patients. Erlotinib plus CT or alone relative to CT is associated with significantly decreased risks of neutropenia and leukopenia in patients with advanced NSCLC (RR, 0.38; 95% CI, 0.21–0.71; P = 0.00; incidence: 9.9 vs. 35.2%) and (RR, 0.32; 95% CI, 0.11–0.93; P = 0.04; incidence: 3.5 vs. 11.6%), respectively. The subgroup analysis by erlotinb with or without CT showed that erlotinib combine with CT have no significance decrease the relative risks of neutropenia or leukopenia (RR, 0.98; 95% CI, 0.78–1.23; P = 0.87; incidence: 26.2 vs. 30.5%) and (RR, 0.81; 95% CI, 0.34–1.95; P = 0.64; incidence: 6.5 vs. 9.3%), respectively. However, erlotinib alone could decrease incidence of neutropenia (RR, 0.14; 95% CI, 0.07–0.27; P = 0.00; incidence: 3.7 vs. 40.8%) or leukopenia (RR, 0.07; 95% CI, 0.01–0.45; P = 0.01; incidence: 0.8 vs. 15.7%). The power analysis

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

PubMed Central

Gao, Sizhi P.; Chang, Qing; Mao, Ninghui; Daly, Laura A.; Vogel, Robert; Chan, Tyler; Liu, Shu Hui; Bournazou, Eirini; Schori, Erez; Zhang, Haiying; Brewer, Monica Red; Pao, William; Morris, Luc; Ladanyi, Marc; Arcila, Maria; Manova-Todorova, Katia; de Stanchina, Elisa; Norton, Larry; Levine, Ross L.; Altan-Bonnet, Gregoire; Solit, David; Zinda, Michael; Huszar, Dennis; Lyden, David; Bromberg, Jacqueline F.

2016-01-01

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non–small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells’ dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC. PMID:27025877

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

PubMed Central

Minari, Roberta; Bordi, Paola

2016-01-01

Osimertinib, third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved in the US and EU for the treatment of EGFR mutant T790M-positive non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs, such as gefitinib, erlotinib and afatinib. Although exciting survival data and response rates have been registered in patients treated with this and other third-generation EGFR-TKIs, unfortunately acquired resistance still occurs after approximately 10 months. Mechanisms determining progression of disease are heterogeneous and not fully understood. EGFR-dependent resistance mechanisms (such as new EGFR mutations), bypass pathway activation [as erb-b2 receptor tyrosine kinase 2 (HER2) or MET amplification] and histological transformation [in small cell lung cancer (SCLC)] have been reported, similarly to previous generation TKIs. Here, we review principle mechanisms of innate and acquired resistance described in literature both in clinical and preclinical settings during NSCLC treatment with third-generation EGFR-TKIs. PMID:28149764

Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash.

PubMed

Steffens, Michael; Paul, Tanusree; Hichert, Vivien; Scholl, Catharina; von Mallek, Dirk; Stelzer, Christoph; Sörgel, Fritz; Reiser, Bärbel; Schumann, Christian; Rüdiger, Stefan; Boeck, Stefan; Heinemann, Volker; Kächele, Volker; Seufferlein, Thomas; Stingl, Julia

2016-03-01

The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5)). The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models.

PubMed

Higgins, Brian; Kolinsky, Kenneth; Smith, Melissa; Beck, Gordon; Rashed, Mohammad; Adames, Violeta; Linn, Michael; Wheeldon, Eric; Gand, Laurent; Birnboeck, Herbert; Hoffmann, Gerhard

2004-06-01

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar

Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition

PubMed Central

Edgar, Kyle A.; Crocker, Lisa; Cheng, Eric; Wagle, Marie-Claire; Wongchenko, Matthew; Yan, Yibing; Wilson, Timothy R.; Dompe, Nicholas; Neve, Richard M.; Belvin, Marcia; Sampath, Deepak; Friedman, Lori S.; Wallin, Jeffrey J.

2014-01-01

Phosphoinositide-3 kinase (PI3K) signaling pathway alterations occur broadly in cancer and PI3K is a promising therapeutic target. Here, we investigated acquired resistance to GDC-0941, a PI3K inhibitor in clinical trials. Colorectal cancer (CRC) cells made to be resistant to GDC-0941 were discovered to secrete amphiregulin, which resulted in increased EGFR/MAPK signaling. Moreover, prolonged PI3K pathway inhibition in cultured cells over a period of months led to a secondary loss of PTEN in 40% of the CRC lines with acquired resistance to PI3K inhibition. In the absence of PI3K inhibitor, these PTEN-null PI3K inhibitor-resistant clones had elevated PI3K pathway signaling and decreased sensitivity to MAPK pathway inhibitors. Importantly, PTEN loss was not able to induce resistance to PI3K inhibitors in the absence of amphiregulin, indicating a multimodal mechanism of acquired resistance. The combination of PI3K and MAPK pathway inhibitors overcame acquired resistance in vitro and in vivo. PMID:25053989

Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition.

PubMed

Edgar, Kyle A; Crocker, Lisa; Cheng, Eric; Wagle, Marie-Claire; Wongchenko, Matthew; Yan, Yibing; Wilson, Timothy R; Dompe, Nicholas; Neve, Richard M; Belvin, Marcia; Sampath, Deepak; Friedman, Lori S; Wallin, Jeffrey J

2014-03-01

Phosphoinositide-3 kinase (PI3K) signaling pathway alterations occur broadly in cancer and PI3K is a promising therapeutic target. Here, we investigated acquired resistance to GDC-0941, a PI3K inhibitor in clinical trials. Colorectal cancer (CRC) cells made to be resistant to GDC-0941 were discovered to secrete amphiregulin, which resulted in increased EGFR/MAPK signaling. Moreover, prolonged PI3K pathway inhibition in cultured cells over a period of months led to a secondary loss of PTEN in 40% of the CRC lines with acquired resistance to PI3K inhibition. In the absence of PI3K inhibitor, these PTEN-null PI3K inhibitor-resistant clones had elevated PI3K pathway signaling and decreased sensitivity to MAPK pathway inhibitors. Importantly, PTEN loss was not able to induce resistance to PI3K inhibitors in the absence of amphiregulin, indicating a multimodal mechanism of acquired resistance. The combination of PI3K and MAPK pathway inhibitors overcame acquired resistance in vitro and in vivo.

Phase II study of erlotinib in patients with advanced biliary cancer.

PubMed

Philip, Philip A; Mahoney, Michelle R; Allmer, Cristine; Thomas, James; Pitot, Henry C; Kim, George; Donehower, Ross C; Fitch, Tom; Picus, Joel; Erlichman, Charles

2006-07-01

Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally. Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash. Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.

Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1.

PubMed

Cheng, Xuewei; Lv, Xia; Qu, Hengyan; Li, Dandan; Hu, Mengmeng; Guo, Wenzhi; Ge, Guangbo; Dong, Ruihua

2017-11-01

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug-drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC 50 values of icotinib and erlotinib against UGT1A1-mediated NCHN- O -glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the K i values of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration-time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition.

Absence of death receptor translocation into lipid rafts in acquired TRAIL-resistant NSCLC cells.

PubMed

Ouyang, Wen; Yang, Chunxu; Zhang, Simin; Liu, Yu; Yang, Bo; Zhang, Junhong; Zhou, Fuxiang; Zhou, Yunfeng; Xie, Conghua

2013-02-01

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a major limitation for its clinical use. The mechanisms of TRAIL resistance have been mostly studied in the context of cell lines that are intrinsically resistant to TRAIL. However, little is known about the molecular alterations that contribute to the development of acquired resistance during treatment with TRAIL. In this study, we established H460R, an isogenic cell line with acquired TRAIL resistance, from the TRAIL‑sensitive human lung cancer cell line H460 to investigate the mechanisms of acquired resistance. The acquired TRAIL‑resistant H460R cells remained sensitive to cisplatin. The mRNA and protein expression levels of death receptor 4 (DR4) and death receptor 5 (DR5) were not altered in either of the TRAIL-treated cell lines. Nevertheless, tests in which the DR4 or DR5 gene was overexpressed or silenced suggest that death receptor expression is necessary but not sufficient for TRAIL‑induced apoptosis. Compared with parental TRAIL-sensitive H460 cells, H460R cells showed a decreased TRAIL-induced translocation of DR4/DR5 into lipid rafts. Further studies showed that nystatin partially prevented lipid raft aggregation and DR4 and DR5 clustering and reduced apoptosis in H460 cells again. Analysis of apoptotic molecules showed that more pro-caspase-8, FADD, caspase-3 and Bid, but less cFLIP in H460 cells than in H460R cells. Our findings suggest that the lack of death receptor redistribution negatively impacts DISC assembly in lipid rafts, which at least partially leads to the development of acquired resistance to TRAIL in H460R cells.

Identification of gene expression profiling associated with erlotinib-related skin toxicity in pancreatic adenocarcinoma patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caba, Octavio, E-mail: ocaba@ujaen.es

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that showed activity against pancreatic ductal adenocarcinoma (PDAC). The drug's most frequently reported side effect as a result of EGFR inhibition is skin rash (SR), a symptom which has been associated with a better therapeutic response to the drug. Gene expression profiling can be used as a tool to predict which patients will develop this important cutaneous manifestation. The aim of the present study was to identify which genes may influence the appearance of SR in PDAC patients. The study included 34 PDAC patients treated with erlotinib: 21 patientsmore » developed any grade of SR, while 13 patients did not (controls). Before administering any chemotherapy regimen and the development of SR, we collected RNA from peripheral blood samples of all patients and studied the differential gene expression pattern using the Illumina microarray platform HumanHT-12 v4 Expression BeadChip. Seven genes (FAM46C, IFITM3, GMPR, DENND6B, SELENBP1, NOL10, and SIAH2), involved in different pathways including regulatory, migratory, and signalling processes, were downregulated in PDAC patients with SR. Our results suggest the existence of a gene expression profiling significantly correlated with erlotinib-induced SR in PDAC that could be used as prognostic indicator in this patients. - Highlights: • Skin rash (SR) is the most characteristic side effect of erlotinib in PDAC patients. • Erlotinib-induced SR has been associated with a better clinical outcome. • Gene expression profiling was used to determine who will develop this manifestation. • 7 genes involved in different pathways were downregulated in PDAC patients with SR. • Our profile correlated with erlotinib-induced SR in PDAC could be used for prognosis.« less

Targeted erlotinib for first-line treatment of advanced non-small cell lung cancer: a budget impact analysis.

PubMed

Bajaj, Preeti S; Veenstra, David L; Goertz, Hans-Peter; Carlson, Josh J

2014-08-01

A recent phase III trial showed that patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor specific EGFR mutations significantly benefit from first-line treatment with erlotinib compared to chemotherapy. This study sought to estimate the budget impact if coverage for EGFR testing and erlotinib as first-line therapy were provided in a hypothetical 500,000-member managed care plan. The budget impact model was developed from a US health plan perspective to evaluate administration of the EGFR test and treatment with erlotinib for EGFR-positive patients, compared to non-targeted treatment with chemotherapy. The eligible patient population was estimated from age-stratified SEER incidence data. Clinical data were derived from key randomized controlled trials. Costs related to drug, administration, and adverse events were included. Sensitivity analyses were conducted to assess uncertainty. In a plan of 500,000 members, it was estimated there would be 91 newly diagnosed advanced NSCLC patients annually; 11 are expected to be EGFR-positive. Based on the testing and treatment assumptions, it was estimated that 3 patients in Scenario 1 and 6 patients in Scenario 2 receive erlotinib. Overall health plan expenditures would increase by $0.013 per member per month (PMPM). This increase is largely attributable to erlotinib drug costs, in part due to lengthened progression-free survival and treatment periods experienced in erlotinib-treated patients. EGFR testing contributes slightly, whereas adverse event costs mitigate the budget impact. The budget impact did not exceed $0.019 PMPM in sensitivity analyses. Coverage for targeted first-line erlotinib therapy in NSCLC likely results in a small budget impact for US health plans. The estimated impact may vary by plan, or if second-line or maintenance therapy, dose changes/interruptions, or impact on patients' quality-of-life were included.

The salvage therapy in lung adenocarcinoma initially harbored susceptible EGFR mutation and acquired resistance occurred to the first-line gefitinib and second-line cytotoxic chemotherapy.

PubMed

Yang, Chih-Jen; Hung, Jen-Yu; Tsai, Ming-Ju; Wu, Kuan-Li; Liu, Ta-Chih; Chou, Shah-Hwa; Lee, Jui-Ying; Hsu, Jui-Sheng; Huang, Ming-Shyan; Chong, Inn-Wen

2017-05-10

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib can provide better efficacy and prolonged progression free survival (PFS) than cytotoxic chemotherapy for metastatic lung non-squamous cell carcinoma harboring susceptible EGFR mutations when used as first-line therapy. Cytotoxic chemotherapy is regarded as being the standard therapy to overcome acquired resistance to an initial EGFR TKI. However, there is currently no consensus on how best to treat patients who develop resistance to both an initial EGFR TKI and chemotherapy. We enrolled stage IV lung adenocarcinoma patients with an EGFR mutation and who had developed acquired resistance to gefitinib and cytotoxic chemotherapy from two university-affiliated hospitals in Taiwan from June 2011 to December 2014. Basic demographic data, included Eastern Cooperative Oncology Group (ECOG) performance status were collected, and the response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. Two hundred and nine patients with mutated EGFR and who took gefitinib as the first-line therapy were identified in the study period, of whom 86 received second-line cytotoxic chemotherapy, and 60 who received third-line therapy were eligible for this study. The patients who received cytotoxic chemotherapy had a significantly higher disease control rate than those who received erlotinib (73% vs. 46%, p = 0.0363), however there were no significant differences in PFS (2.9 months vs. 3.1 months, p = 0.9049) and OS (8.9 months vs. 7.9 months, p = 0.4956). Platinum- or pemetrexed-based chemotherapy provided similar PFS and OS as others did. The only significant poor prognostic factors for OS were old age (≥65 years) (HR = 5.97 [2.65-13.44], p < 0.0001) and poor performance status (ECOG ≥2) (HR = 5.84 [2.61-13.09], p < 0.0001). Retreatment with an EGFR TKI is not inferior to cytotoxic chemotherapy when used as salvage therapy for patients

Socioeconomic and Behavioral Factors Leading to Acquired Bacterial Resistance to Antibiotics in Developing Countries

PubMed Central

Okeke, Iruka N.; Lamikanra, Adebayo

1999-01-01

In developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections. Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread of resistant bacteria; and inadequate surveillance. PMID:10081668

Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer.

PubMed

Philip, Philip A; Mahoney, Michelle R; Allmer, Cristine; Thomas, James; Pitot, Henry C; Kim, George; Donehower, Ross C; Fitch, Tom; Picus, Joel; Erlichman, Charles

2005-09-20

Epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) and ligand expression is frequently seen in hepatocellular cancers (HCCs). Erlotinib (Tarceva, OSI-774; OSI Pharmaceuticals, Melville, NY) is a receptor tyrosine kinase inhibitor with specificity for the EGFR/HER1. The primary objective of this study was to determine the proportion of patients with advanced HCC who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was given continuously at a dose of 150 mg per day orally. Thirty-eight patients with HCC were enrolled. Median age of the patients was 69 years (range, 27 to 83 years). A majority of patients (63%) had an Eastern Cooperative Oncology Group performance status of 1. Forty-seven percent of patients had received prior chemotherapy for advanced HCC. EGFR/HER1 expression was detected in 88% of the patients. Median number of cycles per patient was two (range, 1 to 26). Twelve (32%; CI 95%, 18 to 49) of the 38 patients with HCC were progression-free at 6 months. Three patients had partial radiologic responses of duration of 2, 10, and 11 months, respectively. Disease control was seen in 59% of the patients. Median overall survival time was 13 months. Ten patients (26%) had toxicity-related dose reductions of erlotinib. Grade 3/4 skin toxicity or diarrhea was encountered in five and three patients, respectively. Results of this trial suggest a benefit for EGFR/HER1 blockade with erlotinib in patients with HCC manifested by disease control. Additional studies with erlotinib as a single agent or in combination with other agents are warranted.

Presence and mechanisms of acquired antimicrobial resistance in Belgian Brachyspira hyodysenteriae isolates belonging to different clonal complexes.

PubMed

Mahu, M; Pasmans, F; Vranckx, K; De Pauw, N; Vande Maele, L; Vyt, Philip; Vandersmissen, Tamara; Martel, A; Haesebrouck, F; Boyen, F

2017-08-01

Swine dysentery (SD) is an economically important disease for which antimicrobial treatment still occupies an important place to control outbreaks. However, acquired antimicrobial resistance is increasingly observed in Brachyspira hyodysenteriae. In this study, the Minimal Inhibitory Concentrations (MIC) of six antimicrobial compounds for 30 recent Belgian B. hyodysenteriae isolates were determined using a broth microdilution method. In addition, relevant regions of the 16S rRNA, 23S rRNA and the L3 protein encoding genes were sequenced to reveal mutations associated with acquired resistance. Finally, a phylogeny was reconstructed using minimal spanning tree analysis of multi locus sequence typing of the isolates. For lincomycin, doxycycline, tylosin and tylvalosin, at least 70% of the isolates did not belong to the wild-type population and were considered to have acquired resistance. For valnemulin and tiamulin, this was over 50%. In all isolates with acquired resistance to doxycycline, the G1058C mutation was present in their 16S rRNA gene. All isolates showing acquired resistance to lincomycin and both macrolides displayed the A2058T mutation in their 23S rRNA gene. Other mutations in this gene and the N148S mutation in the L3 protein were present in both wild-type isolates and isolates considered to have acquired resistance. Multi locus sequence analysis revealed a previously undescribed clonal complex, with 4 novel sequence types in which the majority of isolates showed acquired resistance to all tested antimicrobial products. In conclusion, acquired antimicrobial resistance is widespread among Belgian B. hyodysenteriae isolates. The emergence of multi-resistant clonal complexes can pose a threat to swine industry. Copyright © 2017 Elsevier B.V. All rights reserved.

Intrinsic, adaptive and acquired antimicrobial resistance in Gram-negative bacteria.

PubMed

Arzanlou, Mohsen; Chai, Wern Chern; Venter, Henrietta

2017-02-28

Gram-negative bacteria are responsible for a large proportion of antimicrobial-resistant infections in humans and animals. Among this class of bacteria are also some of the most successful environmental organisms. Part of this success is their adaptability to a variety of different niches, their intrinsic resistance to antimicrobial drugs and their ability to rapidly acquire resistance mechanisms. These mechanisms of resistance are not exclusive and the interplay of several mechanisms causes high levels of resistance. In this review, we explore the molecular mechanisms underlying resistance in Gram-negative organisms and how these different mechanisms enable them to survive many different stress conditions. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Treating EGFR mutation resistance in non-small cell lung cancer - role of osimertinib.

PubMed

Mazza, Valentina; Cappuzzo, Federico

2017-01-01

The discovery of mutations in EGFR significantly changed the treatment paradigm of patients with EGFR -mutant non-small cell lung cancer (NSCLC), a particular group of patients with different clinical characteristics and outcome to EGFR -wild-type patients. In these patients, the treatment of choice as first-line therapy is first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, or afatinib. Inevitably, after the initial response, all patients become refractory to these drugs. The most common mechanism of acquired resistance to EGFR-TKIs is the development of a second mutation in exon 20 of EGFR ( T790M ). Osimertinib is a third-generation EGFR-TKI designed for overcoming T790M -mediated resistance. Based on the results of efficacy and tolerability of Phase II and Phase III studies, osimertinib has been approved for treatment of advanced EGFR T790M+ mutation NSCLC following progression on a prior EGFR-TKI. Occurrence of acquired resistance to osimertinib represents an urgent need for additional strategies including combination with other agents, such as other targeted therapies or checkpoint inhibitors, or development of new and more potent compounds.

OUR EXPERIENCES WITH ERLOTINIB IN SECOND AND THIRD LINE TREATMENT PATIENTS WITH ADVANCED STAGE IIIB/ IV NON-SMALL CELL LUNG CANCER

PubMed Central

Mehić, Bakir; Stanetić, Mirko; Tinjić, Ljuljeta; Smoljanović, Vlatka

2008-01-01

HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV openlabel, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders). PMID:19125714

Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model.

PubMed

Tan, Jianlong; Li, Min; Zhong, Wen; Hu, Chengping; Gu, Qihua; Xie, Yali

2017-11-17

Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model. The 1-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 9.82±1.03%, 4.83±0.25%, and 2.62±0.21%, respectively. The 2-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 15.11±2.00%, 5.73±1.31%, and 2.69±0.31%, respectively. Gefitinib exhibited the strongest antitumor activity ( p gefitinib vs. erlotinib =0.005; p gefitinib vs. icotinib =0.002). Notably, erlotinib exhibited a better treatment efficacy than icotinib ( p =0.037). Consistently, immunohistochemical data showed that TKIs differentially inhibit the proliferation of metastatical tumor cells. Gefitinib and erlotinib markedly inhibited the proliferation of tumor cells, while there were more ki-67-positive tumor cells in the icotinib group. Additionally, gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group ( p gefitinib vs. erlotinib =0.995; p gefitinib vs. icotinib =0.028; p erlotinib vs. icotinib =0.042).Altogether, our findings suggest that gefitinib and erlotinib can inhibit the growth of PC-9-luc brain tumors. Gefitinib demonstrated better antitumor activity and penetration rate in brain metastases than erlotinib or icotinib.

The Genomic Basis of Intrinsic and Acquired Antibiotic Resistance in the Genus Serratia

PubMed Central

Sandner-Miranda, Luisa; Vinuesa, Pablo; Cravioto, Alejandro; Morales-Espinosa, Rosario

2018-01-01

Serratia marcescens, a member of the Enterobacteriaceae family, was long thought to be a non-pathogenic bacterium prevalent in environmental habitats. Together with other members of this genus, it has emerged in recent years as an opportunistic nosocomial pathogen causing various types of infections. One important feature of pathogens belonging to this genus is their intrinsic and acquired resistance to a variety of antibiotic families, including β-lactam, aminoglycosides, quinolones and polypeptide antibiotics. The aim of this study was to elucidate which genes participate in the intrinsic and acquired antibiotic resistance of this genus in order to determine the Serratia genus resistome. We performed phylogenomic and comparative genomic analyses using 32 Serratia spp. genomes deposited in the NCBI GenBank from strains isolated from different ecological niches and different lifestyles. S. marcescens strain SmUNAM836, which was previously isolated from a Mexican adult with obstructive pulmonary disease, was included in this study. The results show that most of the antibiotic resistance genes (ARGs) were found on the chromosome, and to a lesser degree, on plasmids and transposons acquired through horizontal gene transfer. Four strains contained the gyrA point mutation in codon Ser83 that confers quinolone resistance. Pathogenic and environmental isolates presented a high number of ARGs, especially genes associated with efflux systems. Pathogenic strains, specifically nosocomial strains, presented more acquired resistance genes than environmental isolates. We may conclude that the environment provides a natural reservoir for antibiotic resistance, which has been underestimated in the medical field. PMID:29867787

Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine.

PubMed

Kim, Tae Hwan; Shin, Soyoung; Kim, Sarah; Bulitta, Jürgen B; Weon, Kwon-Yeon; Joo, Sang Hoon; Ma, Eunsook; Yoo, Sun Dong; Park, Gi-Young; Kwon, Dong Rak; Jeong, Seok Won; Lee, Da Young; Shin, Beom Soo

2017-09-10

Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.

Antimicrobial Resistance in Hospital-Acquired Gram-Negative Bacterial Infections

PubMed Central

Mehrad, Borna; Clark, Nina M.; Zhanel, George G.

2015-01-01

Aerobic gram-negative bacilli, including the family of Enterobacteriaceae and non-lactose fermenting bacteria such as Pseudomonas and Acinetobacter species, are major causes of hospital-acquired infections. The rate of antibiotic resistance among these pathogens has accelerated dramatically in recent years and has reached pandemic scale. It is no longer uncommon to encounter gram-negative infections that are untreatable using conventional antibiotics in hospitalized patients. In this review, we provide a summary of the major classes of gram-negative bacilli and their key mechanisms of antimicrobial resistance, discuss approaches to the treatment of these difficult infections, and outline methods to slow the further spread of resistance mechanisms. PMID:25940252

Oncogenic drivers, targeted therapies, and acquired resistance in non-small-cell lung cancer.

PubMed

Gower, Arjan; Wang, Yisong; Giaccone, Giuseppe

2014-07-01

In the past decade, a shift toward targeted therapies in non-small-cell lung cancer following molecular profiling has dramatically changed the way advanced adenocarcinoma is treated. However, tumor cells inevitably acquire resistance to such therapies, circumventing any sustained clinical benefit. As the genomic classification of lung cancer continues to evolve and as the mechanisms of acquired resistance to targeted therapies become elucidated and more improved target-specific drugs come into sight, the future will see more promising results from the clinic through the development of new therapeutic strategies to overcome, or prevent the development of, resistance for lung cancer patients.

Economic Analysis of First-Line Treatment with Erlotinib in an EGFR-Mutated Population with Advanced NSCLC.

PubMed

Vergnenegre, Alain; Massuti, Bartomeu; de Marinis, Filippo; Carcereny, Enric; Felip, Enriqueta; Do, Pascal; Sanchez, Jose Miguel; Paz-Arez, Luis; Chouaid, Christos; Rosell, Rafael

2016-06-01

The cost-effectiveness of first-line tyrosine kinase inhibitor therapy in epidermal growth factor receptor gene (EGFR)-mutated advanced-stage non-small cell lung cancer (NSCLC) is poorly documented. We therefore conducted a cost-effectiveness analysis of first-line treatment with erlotinib versus standard chemotherapy in European patients with advanced-stage EGFR-mutated NSCLC who were enrolled in the European Erlotinib versus Chemotherapy trial. The European Erlotinib versus Chemotherapy study was a multicenter, open-label, randomized phase III trial performed mainly in Spain, France, and Italy. We based our economic analysis on clinical data and data on resource consumption (drugs, drug administration, adverse events, and second-line treatments) collected during this trial. Utility values were derived from the literature. Incremental cost-effectiveness ratios were calculated for the first-line treatment phase and for the overall strategy from the perspective of the three participating countries. Sensitivity analyses were performed by selecting the main cost drivers. Compared with standard first-line chemotherapy, the first-line treatment with erlotinib was cost saving (€7807, €17,311, and €19,364 for Spain, Italy and France, respectively) and yielded a gain of 0.117 quality-adjusted life-years. A probabilistic sensitivity analysis indicated that, given a willingness to pay at least €90,000 for 1 quality-adjusted life-year, the probability that a strategy of first-line erlotinib would be cost-effective was 100% in France, 100% in Italy, and 99.8% in Spain. This economic analysis shows that first-line treatment with erlotinib, versus standard chemotherapy, is a dominant strategy for EGFR-mutated advanced-stage NSCLC in three European countries. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

PubMed

Magiorakos, A-P; Srinivasan, A; Carey, R B; Carmeli, Y; Falagas, M E; Giske, C G; Harbarth, S; Hindler, J F; Kahlmeter, G; Olsson-Liljequist, B; Paterson, D L; Rice, L B; Stelling, J; Struelens, M J; Vatopoulos, A; Weber, J T; Monnet, D L

2012-03-01

Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. © 2011 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.

Amphibians acquire resistance to live and dead fungus overcoming fungal immunosuppression.

PubMed

McMahon, Taegan A; Sears, Brittany F; Venesky, Matthew D; Bessler, Scott M; Brown, Jenise M; Deutsch, Kaitlin; Halstead, Neal T; Lentz, Garrett; Tenouri, Nadia; Young, Suzanne; Civitello, David J; Ortega, Nicole; Fites, J Scott; Reinert, Laura K; Rollins-Smith, Louise A; Raffel, Thomas R; Rohr, Jason R

2014-07-10

Emerging fungal pathogens pose a greater threat to biodiversity than any other parasitic group, causing declines of many taxa, including bats, corals, bees, snakes and amphibians. Currently, there is little evidence that wild animals can acquire resistance to these pathogens. Batrachochytrium dendrobatidis is a pathogenic fungus implicated in the recent global decline of amphibians. Here we demonstrate that three species of amphibians can acquire behavioural or immunological resistance to B. dendrobatidis. Frogs learned to avoid the fungus after just one B. dendrobatidis exposure and temperature-induced clearance. In subsequent experiments in which B. dendrobatidis avoidance was prevented, the number of previous exposures was a negative predictor of B. dendrobatidis burden on frogs and B. dendrobatidis-induced mortality, and was a positive predictor of lymphocyte abundance and proliferation. These results suggest that amphibians can acquire immunity to B. dendrobatidis that overcomes pathogen-induced immunosuppression and increases their survival. Importantly, exposure to dead fungus induced a similar magnitude of acquired resistance as exposure to live fungus. Exposure of frogs to B. dendrobatidis antigens might offer a practical way to protect pathogen-naive amphibians and facilitate the reintroduction of amphibians to locations in the wild where B. dendrobatidis persists. Moreover, given the conserved nature of vertebrate immune responses to fungi and the fact that many animals are capable of learning to avoid natural enemies, these results offer hope that other wild animal taxa threatened by invasive fungi might be rescued by management approaches based on herd immunity.

Phase 1 Study of Erlotinib Plus Radiation Therapy in Patients With Advanced Cutaneous Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heath, C. Hope; Deep, Nicholas L.; Nabell, Lisle

Purpose: To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Methods and Materials: This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method. Results: The majority of patients were male (87%) and presented with T4 disease (93%). The most common toxicity attributed to erlotinib was a grade 2-3 dermatologic reaction occurring in 100% of the patients, followed by mucositis (87%).more » Diarrhea occurred in 20% of the patients. The 2-year recurrence rate was 26.7%, and mean time to cancer recurrence was 10.5 months. Two-year overall survival was 65%, and disease-free survival was 60%. Conclusions: Erlotinib and radiation therapy had an acceptable toxicity profile in patients with advanced cutaneous squamous cell carcinoma. The disease-free survival in this cohort was comparable to that in historical controls.« less

Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model

PubMed Central

Tan, Jianlong; Li, Min; Zhong, Wen; Hu, Chengping; Gu, Qihua; Xie, Yali

2017-01-01

Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model. The 1-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 9.82±1.03%, 4.83±0.25%, and 2.62±0.21%, respectively. The 2-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 15.11±2.00%, 5.73±1.31%, and 2.69±0.31%, respectively. Gefitinib exhibited the strongest antitumor activity (pgefitinib vs. erlotinib=0.005; pgefitinib vs. icotinib=0.002). Notably, erlotinib exhibited a better treatment efficacy than icotinib (p=0.037). Consistently, immunohistochemical data showed that TKIs differentially inhibit the proliferation of metastatical tumor cells. Gefitinib and erlotinib markedly inhibited the proliferation of tumor cells, while there were more ki-67-positive tumor cells in the icotinib group. Additionally, gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group (pgefitinib vs. erlotinib=0.995; pgefitinib vs. icotinib=0.028; perlotinib vs. icotinib=0.042).Altogether, our findings suggest that gefitinib and erlotinib can inhibit the growth of PC-9-luc brain tumors. Gefitinib demonstrated better antitumor activity and penetration rate in brain metastases than erlotinib or icotinib. PMID:29228726

Stem cell-like ALDHbright cellular states in EGFR-mutant non-small cell lung cancer

PubMed Central

Corominas-Faja, Bruna; Oliveras-Ferraros, Cristina; Cuyàs, Elisabet; Segura-Carretero, Antonio; Joven, Jorge; Martin-Castillo, Begoña; Barrajón-Catalán, Enrique; Micol, Vicente; Bosch-Barrera, Joaquim; Menendez, Javier A

2013-01-01

The enrichment of cancer stem cell (CSC)-like cellular states has not previously been considered to be a causative mechanism in the generalized progression of EGFR-mutant non-small cell lung carcinomas (NSCLC) after an initial response to the EGFR tyrosine kinase inhibitor erlotinib. To explore this possibility, we utilized a pre-clinical model of acquired erlotinib resistance established by growing NSCLC cells containing a TKI-sensitizing EGFR exon 19 deletion (ΔE746-A750) in the continuous presence of high doses of erlotinib. Genome-wide analyses using Agilent 44K Whole Human Genome Arrays were evaluated via bioinformatics analyses through GSEA-based screening of the KEGG pathway database to identify the molecular circuitries that were over-represented in the transcriptomic signatures of erlotinib-refractory cells. The genomic spaces related to erlotinib resistance included a preponderance of cell cycle genes (E2F1, -2, CDC2, -6) and DNA replication-related genes (MCM4, -5, -6, -7), most of which are associated with early lung development and poor prognosis. In addition, metabolic genes such as ALDH1A3 (a candidate marker for lung cancer cells with CSC-like properties) were identified. Thus, we measured the proportion of erlotinib-resistant cells expressing very high levels of aldehyde dehydrogenase (ALDH) activity attributed to ALDH1/3 isoforms. Using flow cytometry and the ALDEFLUOR® reagent, we confirmed that erlotinib-refractory cell populations contained drastically higher percentages (>4500%) of ALDHbright cells than the parental erlotinib-responsive cells. Notably, strong decreases in the percentages of ALDHbright cells were observed following incubation with silibinin, a bioactive flavonolignan that can circumvent erlotinib resistance in vivo. The number of lung cancer spheres was drastically suppressed by silibinin in a dose-dependent manner, thus confirming the ability of this agent to inhibit the self-renewal of erlotinib-refractory CSC-like cells

Combination of gemcitabine and erlotinib inhibits recurrent pancreatic cancer growth in mice via the JAK-STAT pathway

PubMed Central

Chen, Liwen; Zhou, Ding'An; Liu, Zhehao; Huang, Xinhao; Liu, Qianfan; Kang, Yiping; Chen, Zili; Guo, Yuntao; Zhu, Haitao; Sun, Chengyi

2018-01-01

Compared to single gemcitabine treatment, the combination of gemcitabine and erlotinib has shown effective response in patients with locally advanced or metastatic pancreatic cancer. However, the combination therapy has not proven effective in patients with pancreatic cancer after R0 or R1 resection. In the present study, a nude mice model of orthotopic xenotransplantation after tumor resection was established using pancreatic cancer cell lines, BxPC-3 and PANC-1. Mice were divided in four groups (each with n=12) and were treated as follows: the control group received a placebo via intraperitoneal injection (i.p.), while the other three groups were treated with gemcitabine (50 mg/kg i.p., twice a week), erlotinib (50 mg/kg oral gavage, once every three days), and combined treatment of gemcitabine and erlotinib, respectively. The treatment lasted for 21 days, after which all mice were sacrificed and tumors were examined ex vivo. We determined that the combination of gemcitabine and erlotinib inhibited recurrent tumor growth and induced apoptosis in vivo by downregulating phosphorylation levels of JAKs and STATs, which in turn downregulated the downstream proteins HIF-1α and cyclin D1, and upregulated caspase-9 and caspase-3 expression. To sum up, the combination of gemcitabine with erlotinib was effective in treating patients with pancreatic cancer after R0 or R1 resection. PMID:29328487

Pattern of secondary acquired drug resistance to antituberculosis drug in Mumbai, India--1991-1995.

PubMed

Chowgule, R V; Deodhar, L

1998-01-01

A retrospective observational study was conducted to find out whether secondary acquired drug resistance to isoniazid and ethambutol is high and to rifamycin and pyrazinamide is low, as is commonly believed in India. There were 2033 patients, whose sputum samples (6099) were reviewed from a specimen registry of the microbiology laboratory for the years 1991 to 1995. Of these, 521 (25.6%) patients [335 males and 186 females; age ranged from 11 to 75 years] had sputum positive culture and sensitivity for acid-fast bacilli (AFB). The drug resistance patterns in our study were: isoniazid (H) 15%, rifamycin (R) 66.8%, pyrazinamide (Z) 72.2%, ethambutol (E) 8.4%, streptomycin (S) 53.6%, cycloserine (C) 39.2% kanamycin (K) 25.1% and ethionamide (Eth) 65.3%. The resistance to streptomycin showed a significant fall over a year while there was a rise in resistance to cycloserine and kanamycin which is significant. The rate of secondary acquired resistance of isoniazid and ethambutol was low, and the rate of secondary acquired resistance to rifamycin and pyrazinamide was high, which is contarary to the common belief regarding these drugs in India. This implies that isoniazid is still a valuable drug in the treatment of multidrug resistance in India.

Plasma and pleural fluid pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small-cell lung cancer with pleural effusion.

PubMed

Masago, Katsuhiro; Togashi, Yosuke; Fukudo, Masahide; Terada, Tomohiro; Irisa, Kaoru; Sakamori, Yuichi; Kim, Young Hak; Mio, Tadashi; Inui, Ken-Ichi; Mishima, Michiaki

2011-09-01

Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects. Copyright © 2011. Published by Elsevier Inc.

Gefitinib provides similar effectiveness and improved safety than erlotinib for advanced non-small cell lung cancer: A meta-analysis.

PubMed

Zhang, Wenxiong; Wei, Yiping; Yu, Dongliang; Xu, Jianjun; Peng, Jinhua

2018-04-01

The epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib are effective for advanced non-small cell lung cancer (NSCLC). This meta-analysis compared their effectiveness and safety. We searched systematically in PubMed, ScienceDirect, The Cochrane Library, Scopus, Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar for relevant clinical trials regarding gefitinib versus erlotinib for NSCLC. Antitumor effectiveness (overall survival [OS], progression-free survival [PFS], objective response rate [ORR] and disease control rate [DCR]) and adverse effects [AEs]) were assessed. Forty studies comprising 9376 participants were included. The results suggested that gefitinib and erlotinib are effective for advanced NSCLC with comparable PFS (95% confidence intervals [CI]: 0.98-1.11, P = .15), OS (95% CI: 0.93-1.19, P = .45), ORR (95% CI: 0.99-1.16, P = .07), and DCR (95% CI: 0.92-1.03, P = .35). For erlotinib, dose reduction was significantly more frequent (95% CI: 0.10-0.57, P = .001) as were grade 3 to 5 AEs (95% CI: 0.36-0.79, P = .002). In the subgroup analysis, the erlotinib group had a significant higher rate and severity of skin rash, nausea/vomiting, fatigue, and stomatitis. Gefitinib was proven to be the better choice for advanced NSCLC, with equal antitumor effectiveness and fewer AEs compared with erlotinib. Further large-scale, well-designed randomized controlled trials are warranted to confirm our validation.

Phase I dose escalation study of capecitabine and erlotinib concurrent with radiation in locally advanced pancreatic cancer.

PubMed

Jiang, Yixing; Mackley, Heath B; Kimchi, Eric T; Zhu, Junjia; Gusani, Niraj; Kaifi, Jussuf; Staveley-O'Carroll, Kevin F; Belani, Chandra P

2014-07-01

Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. The median survival of locally advanced nonoperable disease is approximately 9 months. 5-FU-based chemoradiotherapy has been the standard treatment. However, the survival benefit of this approach is modest. To improve the efficacy of 5-FU-based chemoradiation therapy, we evaluated the safety and feasibility of the combination of capecitabine and erlotinib with radiotherapy in this group of patients. A traditional "3 + 3" dose escalation design was adopted in the study. A total of four dose levels were designed. For safety purpose, a minus I dose level (-I) was also planned. The -I level consisted of capecitabine 600 mg/m² and erlotinib 50 mg daily, and the remaining four dose levels were as follows: level I: capecitabine 600 mg/m² bid (twice daily); level II: 700 mg/m² bid; level III: 825 mg/m² bid; and level IV: 925 mg/m² bid. Erlotinib was administered at 100 mg daily at all dose levels. Erlotinib and capceitabine were given continuously Monday through Friday concurrent with radiotherapy (50.4 Gy in 28 fractions). A total of 18 patients were consented. Fifteen patients were enrolled and completed therapy. No dose-limiting toxicity was observed. The most frequent side effects were lymphopenia, nausea, vomiting, diarrhea, electrolyte imbalances, and skin rashes. The majority of the toxicities were grade 1 and 2. No objective response was observed. The median progression-free survival was 0.59 years (95 % CI 0.31-1.1), and the median overall survival was 1.1 years (95 % CI 0.62-1.59). The combination of capecitabine and erlotinib with radiotherapy in locally advanced pancreatic cancer is well tolerated and feasible at the dose level of capecitabine 925 mg/m² bid and erlotinib 100 mg daily.

Management of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practice.

PubMed

Diaz Beveridge, Robert; Alcolea, Vicent; Aparicio, Jorge; Segura, Ángel; García, Jose; Corbellas, Miguel; Fonfría, María; Giménez, Alejandra; Montalar, Joaquin

2014-01-10

The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.

Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis

PubMed Central

El Sissy, Carine; Bachelier-Bassi, Sophie; Scemla, Anne; Quesne, Gilles; Sitterlé, Emilie; Legendre, Christophe; Lortholary, Olivier; Bougnoux, Marie-Elisabeth

2015-01-01

Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis. PMID:26525799

Population pharmacokinetics/pharmacodynamics of erlotinib and pharmacogenomic analysis of plasma and cerebrospinal fluid drug concentrations in Japanese patients with non-small cell lung cancer.

PubMed

Fukudo, Masahide; Ikemi, Yasuaki; Togashi, Yosuke; Masago, Katsuhiro; Kim, Young Hak; Mio, Tadashi; Terada, Tomohiro; Teramukai, Satoshi; Mishima, Michiaki; Inui, Ken-Ichi; Katsura, Toshiya

2013-07-01

Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420. A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated. The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p < 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p < 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median

Free radicals mediate systemic acquired resistance.

PubMed

Wang, Caixia; El-Shetehy, Mohamed; Shine, M B; Yu, Keshun; Navarre, Duroy; Wendehenne, David; Kachroo, Aardra; Kachroo, Pradeep

2014-04-24

Systemic acquired resistance (SAR) is a form of resistance that protects plants against a broad spectrum of secondary infections. However, exploiting SAR for the protection of agriculturally important plants warrants a thorough investigation of the mutual interrelationships among the various signals that mediate SAR. Here, we show that nitric oxide (NO) and reactive oxygen species (ROS) serve as inducers of SAR in a concentration-dependent manner. Thus, genetic mutations that either inhibit NO/ROS production or increase NO accumulation (e.g., a mutation in S-nitrosoglutathione reductase [GSNOR]) abrogate SAR. Different ROS function additively to generate the fatty-acid-derived azelaic acid (AzA), which in turn induces production of the SAR inducer glycerol-3-phosphate (G3P). Notably, this NO/ROS→AzA→G3P-induced signaling functions in parallel with salicylic acid-derived signaling. We propose that the parallel operation of NO/ROS and SA pathways facilitates coordinated regulation in order to ensure optimal induction of SAR. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.

PubMed

Lindsay, Danika; Garvey, Colleen M; Mumenthaler, Shannon M; Foo, Jasmine

2016-08-01

Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs) are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i) combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii) sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii) strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the clinic.

Phase II trial of epidermal growth factor ointment for patients with Erlotinib-related skin effects.

PubMed

Hwang, In Gyu; Kang, Jung Hun; Oh, Sung Yong; Lee, Suee; Kim, Sung-Hyun; Song, Ki-Hoon; Son, Choonhee; Park, Min Jae; Kang, Myung Hee; Kim, Hoon Gu; Lee, Jeeyun; Park, Young Suk; Sun, Jong Mu; Kim, Hyun Jung; Kim, Chan Kyu; Yi, Seong Yoon; Jang, Joung-Soon; Park, Keunchil; Kim, Hyo-Jin

2016-01-01

The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib-related skin effects (ERSEs). This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to ≤ grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks. Fifty-two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2%) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 ± 0.83 to 1.13 ± 0.89 and 1.52 ± 0.84 to 0.67 ± 0.90, respectively (p < 0.001). The most common reason for discontinuing the study was progression of cancer (37%). Based on the results, the EGF ointment is effective for ERSEs, regardless of gender, age, type of tumor, and dosage of erlotinib. The EGF ointment evenly improved all kinds of symptoms of ERSEs. ClinicalTrials.gov identifier: NCT01593995.

Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib.

PubMed

Ho, Chao-Chi; Liao, Wei-Yu; Lin, Chih-An; Shih, Jin-Yuan; Yu, Chong-Jen; Chih-Hsin Yang, James

2017-03-01

AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment. Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib. Tumor genotyping was done by matrix-assisted laser desorption ionization-time of flight mass spectrometry. EGFR, AKT, MEK, and ERK phosphorylation were determined. An anchorage-dependent colony formation assay was used for drug sensitivity. An acquired mutation, BRAF V600E, was found in the patient at the time of progression while being treated with osimertinib. Cells grown from malignant pleural effusion were sensitive to BRAF V600E inhibitor and were more vulnerable to a combination treatment with osimertinib. A potential mechanism of acquired resistance to osimertinib in patients with T790M is through the BRAF pathway. Simultaneous blockade of the BRAF and EGFR had a significant inhibitory effect. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

TUSC2(FUS1)-erlotinib Induced Vulnerabilities in Epidermal Growth Factor Receptor(EGFR) Wildtype Non-small Cell Lung Cancer(NSCLC) Targeted by the Repurposed Drug Auranofin.

PubMed

Xiaobo, Cao; Majidi, Mourad; Feng, Meng; Shao, Ruping; Wang, Jing; Zhao, Yang; Baladandayuthapani, Veerabhadran; Song, Juhee; Fang, Bingliang; Ji, Lin; Mehran, Reza; Roth, Jack A

2016-11-15

Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF.

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

PubMed Central

Sutiman, Natalia; Zhang, Zhenxian; Tan, Eng Huat; Ang, Mei Kim; Tan, Shao-Weng Daniel; Toh, Chee Keong; Ng, Quan Sing; Chowbay, Balram; Lim, Wan-Teck

2016-01-01

Purpose This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). Methods This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. Results The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Conclusions Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. Trial Registration ClinicalTrials.gov NCT00702182 PMID:27135612

Combination of erlotinib and EGCG induces apoptosis of head and neck cancers through posttranscriptional regulation of Bim and Bcl-2.

PubMed

Haque, Abedul; Rahman, Mohammad Aminur; Chen, Zhuo Georgia; Saba, Nabil F; Khuri, Fadlo R; Shin, Dong M; Ruhul Amin, A R M

2015-07-01

Combinatorial approaches using two or more compounds are gaining increasing attention for cancer therapy. We have previously reported that the combination of the EGFR-TKI erlotinib and epigallocatechin-3-gallate (EGCG) exhibited synergistic chemopreventive effects in head and neck cancers by inducing the expression of Bim, p21, p27, and by inhibiting the phosphorylation of ERK and AKT and expression of Bcl-2. In the current study, we further investigated the mechanism of regulation of Bim, Bcl-2, p21 and p27, and their role in apoptosis. shRNA-mediated silencing of Bim significantly inhibited apoptosis induced by the combination of erlotinib and EGCG (p = 0.005). On the other hand, overexpression of Bcl-2 markedly protected cells from apoptosis (p = 0.003), whereas overexpression of constitutively active AKT only minimally protected cells from apoptosis induced by the combination of the two compounds. Analysis of mRNA expression by RT-PCR revealed that erlotinib, EGCG and their combination had no significant effects on the mRNA expression of Bim, p21, p27 or Bcl-2 suggesting the post-transcriptional regulation of these molecules. Furthermore, we found that erlotinib or the combination of EGCG and erlotinib inhibited the phosphorylation of Bim and stabilized Bim after inhibition of protein translation by cycloheximide. Taken together, our results strongly suggest that the combination of erlotinib and EGCG induces apoptosis of SCCHN cells by regulating Bim and Bcl-2 at the posttranscriptional level.

Primary and acquired drug resistance in Mycobacterium tuberculosis strains in western region of Libyan Arab Jamahiriya.

PubMed

Elghoul, M T; Joshi, R M; Rizghalla, T

1989-10-01

Drug resistance in Mycobacterium tuberculosis strains prevalent in the Western Region of Libyan Arab Jamahiriya was studied for the years 1984, 1985 and 1986 at the regional tuberculosis control centre at Gurgi, Tripoli. Records of resistance to streptomycin, isoniazid, ethambutol and rifampicin were analysed. Whereas primary drug resistance was observed in 5.1%, 19.5% and 3.8%, acquired drug resistance was found in 12.2%, 34.0% and 15.3% of the strains in 1984, 1985 and 1986 respectively. Only 3 out of 598 strains (1.2%) were found to show acquired resistance to rifampicin. No primary resistance to rifampicin was observed. The situation of drug resistance in pulmonary tuberculosis in the Jamahiriya is discussed.

Erlotinib as a single agent in select subsets of patients with advanced non-small-cell lung cancer.

PubMed

Carrión, Ramón Pérez; Gracián, Antonio Cubillo; Hernandez, Pedro Salinas

2007-07-01

Erlotinib is an orally active inhibitor of the epidermal growth factor receptor that is effective for the treatment of non-small-cell lung cancer (NSCLC). Patients with a poor performance status (PS) of 2 constitute up to 40% of advanced NSCLC. This group of patients have a lower life expectancy and are thought to have a greater degree of treatment-related toxicity. The clinical benefit on 238 patients with poor PS included in an open-label, nonrandomized, phase II trial of erlotinib in advanced/metastatic NSCLC was 57.58% defined as complete response plus partial response plus stable disease. Median time to progression was 2.9 months. This review will summarize available data about erlotinib on patients with a PS of 2.

Acquired Flucytosine Resistance during Combination Therapy with Caspofungin and Flucytosine for Candida glabrata Cystitis.

PubMed

Charlier, Caroline; El Sissy, Carine; Bachelier-Bassi, Sophie; Scemla, Anne; Quesne, Gilles; Sitterlé, Emilie; Legendre, Christophe; Lortholary, Olivier; Bougnoux, Marie-Elisabeth

2016-01-01

Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Characterization of fecal vancomycin-resistant enterococci with acquired and intrinsic resistance mechanisms in wild animals, Spain.

PubMed

Lozano, Carmen; Gonzalez-Barrio, David; Camacho, Maria Cruz; Lima-Barbero, Jose Francisco; de la Puente, Javier; Höfle, Ursula; Torres, Carmen

2016-11-01

The objectives were to evaluate the presence of vancomycin-resistant enterococci with acquired (VRE-a) and intrinsic (VRE-i) resistance mechanisms in fecal samples from different wild animals, and analyze their phenotypes and genotypes of antimicrobial resistance. A total of 348 cloacal/rectal samples from red-legged partridges (127), white storks (81), red kites (59), and wild boars (81) (June 2014/February 2015) were inoculated in Slanetz-Bartley agar supplemented with vancomycin (4 μg/mL). We investigated the susceptibility to 12 antimicrobials and the presence of 19 antimicrobial resistance and five virulence genes. In addition, we performed multilocus sequence typing, detection of IS16 and studied Tn1546 structure. One VRE-a isolate was identified in one wild boar. This isolate was identified as Enterococcus faecium, harbored vanA gene included into Tn1546 (truncated with IS1542/IS1216), and belonged to the new ST993. This isolate contained the erm(A), erm(B), tet(M), dfrG, and dfrK genes. Neither element IS16 nor the studied virulence genes were detected. Ninety-six VRE-i isolates were identified (89 Enterococcus gallinarum and seven Enterococcus casseliflavus), with the following prevalence: red kites (71.2 %), white storks (46.9 %), red-legged partridges (7.9 %), and wild boars (4.9 %). Most E. gallinarum isolates showed resistance to tetracycline (66.3 %) and/or erythromycin (46.1 %). High-level resistance to aminoglycosides was present among our VRE-i isolates: kanamycin (22.9 %), streptomycin (11.5 %), and gentamicin (9.4 %). In general, VRE-i isolates of red kites showed higher rates of resistance for non-glycopeptide agents than those of other animal species. The dissemination of acquired resistance mechanisms in natural environments could have implications in the global spread of resistance with public health implications.

Dual phosphoproteomics and chemical proteomics analysis of erlotinib and gefitinib interference in acute myeloid leukemia cells.

PubMed

Weber, Christoph; Schreiber, Thiemo B; Daub, Henrik

2012-02-02

Small molecule inhibitors of protein kinases have emerged as a major class of therapeutic agents for the treatment of hematological malignancies. Both in vitro studies and patient case reports suggest therapeutic potential of the clinical kinase inhibitors erlotinib and gefitinib in acute myeloid leukemia (AML). The drugs' cellular modes of action in AML warrant further investigation as their primary therapeutic target, the epidermal growth factor receptor, is not expressed. We therefore performed SILAC-based quantitative mass spectrometry analyses to a depth of 10,975 distinct phosphorylation sites to characterize the phosphoproteome of KG1 AML cells and its regulation upon erlotinib and gefitinib treatment. Less than 50 site-specific phosphorylations changed significantly, indicating rather specific interference with AML cell signaling. Many drug-induced changes occurred within a network of tyrosine phosphorylated proteins that included Src family kinases (SFKs) and the tyrosine kinases Btk and Syk. We further performed quantitative chemical proteomics in KG1 cell extracts and identified SFKs and Btk as direct cellular targets of both erlotinib and gefitinib. Taken together, our data suggest that cellular perturbation of SFKs and/or Btk translates into rather specific signal transduction inhibition, which in turn contributes to the antileukemic activity of erlotinib and gefitinib in AML. Copyright © 2011 Elsevier B.V. All rights reserved.

Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity.

PubMed

Bao, Bin; Mitrea, Cristina; Wijesinghe, Priyanga; Marchetti, Luca; Girsch, Emily; Farr, Rebecca L; Boerner, Julie L; Mohammad, Ramzi; Dyson, Greg; Terlecky, Stanley R; Bollig-Fischer, Aliccia

2017-03-10

Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c.

Bayesian model of signal rewiring reveals mechanisms of gene dysregulation in acquired drug resistance in breast cancer

PubMed Central

Azad, A. K. M.; Keith, Jonathan M.

2017-01-01

Small molecule inhibitors, such as lapatinib, are effective against breast cancer in clinical trials, but tumor cells ultimately acquire resistance to the drug. Maintaining sensitization to drug action is essential for durable growth inhibition. Recently, adaptive reprogramming of signaling circuitry has been identified as a major cause of acquired resistance. We developed a computational framework using a Bayesian statistical approach to model signal rewiring in acquired resistance. We used the p1-model to infer potential aberrant gene-pairs with differential posterior probabilities of appearing in resistant-vs-parental networks. Results were obtained using matched gene expression profiles under resistant and parental conditions. Using two lapatinib-treated ErbB2-positive breast cancer cell-lines: SKBR3 and BT474, our method identified similar dysregulated signaling pathways including EGFR-related pathways as well as other receptor-related pathways, many of which were reported previously as compensatory pathways of EGFR-inhibition via signaling cross-talk. A manual literature survey provided strong evidence that aberrant signaling activities in dysregulated pathways are closely related to acquired resistance in EGFR tyrosine kinase inhibitors. Our approach predicted literature-supported dysregulated pathways complementary to both node-centric (SPIA, DAVID, and GATHER) and edge-centric (ESEA and PAGI) methods. Moreover, by proposing a novel pattern of aberrant signaling called V-structures, we observed that genes were dysregulated in resistant-vs-sensitive conditions when they were involved in the switch of dependencies from targeted to bypass signaling events. A literature survey of some important V-structures suggested they play a role in breast cancer metastasis and/or acquired resistance to EGFR-TKIs, where the mRNA changes of TGFBR2, LEF1 and TP53 in resistant-vs-sensitive conditions were related to the dependency switch from targeted to bypass signaling links

Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis.

PubMed

Togashi, Yosuke; Masago, Katsuhiro; Fukudo, Masahide; Terada, Tomohiro; Ikemi, Yasuaki; Kim, Young Hak; Fujita, Shiro; Irisa, Kaoru; Sakamori, Yuichi; Mio, Tadashi; Inui, Ken-Ichi; Mishima, Michiaki

2010-05-01

Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment.

PubMed

Parra-Guillen, Zinnia P; Berger, Peter B; Haschke, Manuel; Donzelli, Massimiliano; Winogradova, Daria; Pfister, Bogumila; Früh, Martin; Gillessen, Silke; Krähenbühl, Stephan; Kloft, Charlotte; Joerger, Markus

2017-10-01

Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R 2  = 0.960, p < 0.0001), OSI-420 (R 2  = 0.971, p < 0.0001), midazolam (R 2  = 0.995, p < 0.0001) and caffeine (R 2  = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R 2  = 0.33, p = 0.048), while midazolam clearance was not (R 2  = -0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t-test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Radiation recall gastritis secondary to combination of gemcitabine and erlotinib in pancreatic cancer and response to PPI - a case report.

PubMed

Choi, Seong Ji; Kim, Hyo Jung; Kim, Jae Seon; Bak, Young-Tae; Kim, Jun Suk

2016-08-02

Radiation recall gastritis is rare but can be induced after concurrent chemoradiation for pancreatic cancer. We report a patient with pancreatic cancer who developed radiation-recall gastritis related to a combination of gemcitabine and erlotinib. A 54-year-old female with unresectable pancreatic cancer received gemcitabine in combination with radiation therapy followed by chemotherapy with gemcitabine and erlotinib. After completing 2 cycles of chemotherapy, the patient had epigastric pain, nausea, and vomiting. Abdominal computed tomography (CT) scan revealed diffuse wall thickening of the stomach, and esophagogastroduodenoscopy (EGD) showed multiple gastric ulcers. The patient was treated with proton pump inhibitors (PPI) and was continued on maintenance chemotherapy. Two months later, the patient presented with the similar symptoms and persistent gastric ulcers were observed during subsequent EGD. Nevertheless, the patient's symptom had resolved with PPI therapy. Thus, the patient underwent maintenance chemotherapy with gemcitabine and erlotinib for additional 4 cycles. Eventually, follow-up abdominal CT Scan and EGD at 6 months demonstrated resolution of the gastric ulcers. Physicians should be aware of the possibility of radiation recall gastritis associated with a combination of gemcitabine and erlotinib. Administration of PPIs may mitigate the adverse effects of gemcitabine and erlotinib in the presence of radiation recall gastritis; however further studies are warranted.

Erlotinib for Patients with EGFR Wild-Type Metastatic NSCLC: a Retrospective Biomarkers Analysis.

PubMed

Inno, Alessandro; Di Noia, Vincenzo; Martini, Maurizio; D'Argento, Ettore; Di Salvatore, Mariantonietta; Arena, Vincenzo; Schinzari, Giovanni; Orlandi, Armando; Larocca, Luigi Maria; Cassano, Alessandra; Barone, Carlo

2018-03-20

Erlotinib is approved for the treatment of patients with EGFR mutation positive, metastatic NSCLC. It is also approved as second/third line therapy for EGFR mutation negative patients, but in this setting the benefit of erlotinib is modest and there is no validated biomarker for selecting EGFR wild-type patients who may benefit the most from the treatment. We retrospectively assessed EGFR and K-RAS mutational status, and EGFR, c-MET and IGF1-R expression in tumor samples of 72 patients with metastatic NSCLC treated with erlotinib after at least one prior line of chemotherapy, from 2008 to 2012. We analyzed the association between biomarkers and outcome (RR, PFS, and OS). EGFR mutated patients achieved a better RR (56% vs 8%, p = .002), PFS (10 vs 3 months, HR 0.53, p = 0.48) and OS (20 vs 6 months, HR 0.55, p = .07), compared to EGFR wild-type patients. Among 63 EGFR wild-type patients, those with EGFR high-expression had a better outcome in terms of RR (40% vs 2%, p = .002), PFS (7.5 vs 2 months, HR 0.45, p = .007) and OS (30 vs 5 months, HR 0.34, p < .001) compared to patients with EGFR intermediate or low/negative-expression. IGF1-R expression, c-MET expression and K-RAS mutational status did not significantly affect the outcome; however, no patients with K-RAS mutation or c-MET high-expression achieved an objective response. In patients with metastatic, chemo-refractory EGFR wild-type NSCLC, EGFR high-expression may represent a positive predictor of activity for erlotinib, whereas K-RAS mutation and c-MET high-expression may predict lack of activity. These findings deserve further prospective evaluation.

Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.

PubMed

Li, Jiannong; Bennett, Keiryn; Stukalov, Alexey; Fang, Bin; Zhang, Guolin; Yoshida, Takeshi; Okamoto, Isamu; Kim, Jae-Young; Song, Lanxi; Bai, Yun; Qian, Xiaoning; Rawal, Bhupendra; Schell, Michael; Grebien, Florian; Winter, Georg; Rix, Uwe; Eschrich, Steven; Colinge, Jacques; Koomen, John; Superti-Furga, Giulio; Haura, Eric B

2013-11-05

We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein-protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems-level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14-protein core network critical to the viability of multiple EGFR-mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR-mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance.

The Risk of Neutropenia and Leukopenia in Advanced Non-Small Cell Lung Cancer Patients Treated With Erlotinib: A Prisma-Compliant Systematic Review and Meta-Analysis.

PubMed

Zhou, Jian-Guo; Tian, Xu; Cheng, Long; Zhou, Quan; Liu, Yuan; Zhang, Yu; Bai, Yu-ju; Ma, Hu

2015-10-01

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a critical member of systemic therapy for advanced non-small-cell lung cancer (NSCLC). Erlotinib is the first-generation EGFR-TKIs, the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations. However, the safety of erlotinib plus chemotherapy (CT) or erlotinib alone for advanced NSCLC remains controversial. We carried out a systematic meta-analysis to determine the overall risk of neutropenia and leukopenia associated with erlotinib. PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. RR with 95% CIs for neutropenia and leukopenia were all extracted. The random-effects model was used to calculate pooled RRs and 95% CIs. Power calculation was performed using macro embedded in SAS software after all syntheses were conducted. We identified 12 eligible studies involving 3932 patients. Erlotinib plus CT or alone relative to CT is associated with significantly decreased risks of neutropenia and leukopenia in patients with advanced NSCLC (RR, 0.38; 95% CI, 0.21-0.71; P = 0.00; incidence: 9.9 vs. 35.2%) and (RR, 0.32; 95% CI, 0.11-0.93; P = 0.04; incidence: 3.5 vs. 11.6%), respectively. The subgroup analysis by erlotinib with or without CT showed that erlotinib combine with CT have no significance decrease the relative risks of neutropenia or leukopenia (RR, 0.98; 95% CI, 0.78-1.23; P = 0.87; incidence: 26.2 vs. 30.5%) and (RR, 0.81; 95% CI, 0.34-1.95; P = 0.64; incidence: 6.5 vs. 9.3%), respectively. However, erlotinib alone could decrease incidence of neutropenia (RR, 0.14; 95% CI, 0.07-0.27; P = 0.00; incidence: 3.7 vs. 40.8%) or leukopenia (RR, 0.07; 95% CI, 0.01-0.45; P = 0.01; incidence: 0.8 vs. 15.7%). The power analysis suggests that a power of 61.31% was determined

Staphylococcus aureus PBP4 Is Essential for β-Lactam Resistance in Community-Acquired Methicillin-Resistant Strains▿

PubMed Central

Memmi, Guido; Filipe, Sergio R.; Pinho, Mariana G.; Fu, Zhibiao; Cheung, Ambrose

2008-01-01

Recent cases of infections caused by community-acquired methicillin-resistant Staphylococcus aureus (MRSA) (CA-MRSA) strains in healthy individuals have raised concerns worldwide. CA-MRSA strains differ from hospital-acquired MRSAs by virtue of their genomic background and increased virulence in animal models. Here, we show that in two common CA-MRSA isolates, USA300 and MW2 (USA400), a loss of penicillin binding protein 4 (PBP4) is sufficient to cause a 16-fold reduction in oxacillin and nafcillin resistance, thus demonstrating that mecA, encoding PBP2A, is not the sole determinant of methicillin resistance in CA-MRSA. The loss of PBP4 was also found to severely affect the transcription of PBP2 in cells after challenge with oxacillin, thus leading to a significant decrease in peptidoglycan cross-linking. Autolysis, which is commonly associated with the killing mechanism of penicillin and β-lactams, does not play a role in the reduced resistance phenotype associated with the loss of PBP4. We also showed that cefoxitin, a semisynthetic β-lactam that binds irreversibly to PBP4, is synergistic with oxacillin in killing CA-MRSA strains, including clinical CA-MRSA isolates. Thus, PBP4 represents a major target for drug rediscovery against CA-MRSA, and a combination of cefoxitin and synthetic penicillins may be an effective therapy for CA-MRSA infections. PMID:18725435

Emergence of CTNNB1 mutation at acquired resistance to KIT inhibitor in metastatic melanoma.

PubMed

Cho, J; Kim, S Y; Kim, Y J; Sim, M H; Kim, S T; Kim, N K D; Kim, K; Park, W; Kim, J H; Jang, K-T; Lee, J

2017-10-01

The KIT inhibitor, imatinib, has shown promising efficacy in patients with KIT-mutated melanoma; however, acquisition of resistance to imatinib occurs rapidly in the majority of patients. The mechanisms of acquired resistance to imatinib in melanoma remain unclear. We analyzed biopsy samples from paired baseline and post-treatment tumor lesions in one patient with KIT-mutated melanoma who had had an initial objective tumor regression in response to imatinib treatment followed by disease progression 8 months later. Targeted deep sequencing from post-treatment biopsy samples detected an additional mutation in CTNNB1 (S33C) with original KIT L576P mutation. We examined the functional role of the additional CTNNB1 S33C mutation in resistance to imatinib indirectly using the Ba/F3 cell model. Ba/F3 cell lines transfected with both the L576P KIT mutation and the CTNNB1 S33C mutation demonstrated no growth inhibition despite imatinib treatment, whereas growth inhibition was observed in the Ba/F3 cell line transfected with the L576 KIT mutation alone. We report the first identification of the emergence of a CTNNB1 mutation that can confer acquired resistance to imatinib. Further investigation into the causes of acquired resistance to imatinib will be essential to improve the prognosis for patients with KIT-mutated melanoma.

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis.

PubMed

Wang, Yuanzhong; Zhou, Dujin; Phung, Sheryl; Warden, Charles; Rashid, Rumana; Chan, Nymph; Chen, Shiuan

2017-02-21

Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.

Avenanthramide biosynthesis in oat cultivars treated with systemic acquired resistance elicitors

USDA-ARS?s Scientific Manuscript database

The synthetic systemic acquired resistance elicitor benzothiadiazole (BTH) has been shown to elicit avenanthramide biosynthesis in the oat cultivar ‘Belle’. This report investigates the response of multiple oat cultivars to BTH as well as 2,6- dichloroisonicotinic acid (INA) at different growth stag...

Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas.

PubMed

Yin, Jinlong; Jung, Ji-Eun; Choi, Sun Il; Kim, Sung Soo; Oh, Young Taek; Kim, Tae-Hoon; Choi, Eunji; Lee, Sun Joo; Kim, Hana; Kim, Eun Ok; Lee, Yu Sun; Chang, Hee Jin; Park, Joo Yong; Kim, Yeejeong; Yun, Tak; Heo, Kyun; Kim, Youn-Jae; Kim, Hyunggee; Kim, Yun-Hee; Park, Jong Bae; Choi, Sung Weon

2018-02-01

Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC. Copyright © 2017 Elsevier B.V. All rights reserved.

OPTIMAL and ENSURE trials-based combined cost-effectiveness analysis of erlotinib versus chemotherapy for the first-line treatment of Asian patients with non-squamous non-small-cell lung cancer

PubMed Central

Zhang, Pengfei; Hutton, David; Li, Qiu

2018-01-01

Objectives Erlotinib, the first generation of epidermoid growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been recommended as an essential treatment in patients with non-small-cell lung cancer (NSCLC) with EGFR mutation. Although it has improved progression-free survival (PFS), overall survival (OS) was limited and erlotinib can be expensive. This cost-effectiveness analysis compares erlotinib monotherapy with gemcitabine-included doublet chemotherapy. Setting First-line treatment of Asian patients with NSCLC with EGFR mutation. Methods A Markov model was created based on the results of the ENSURE (NCT01342965) and OPTIMAL (CTONG-0802) trials which evaluated erlotinib and chemotherapy. The model simulates cancer progression and all causes of death. All medical costs were calculated from the perspective of the Chinese healthcare system. Main outcome measures The primary outcomes are costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Results The combined PFS was 11.81 months and 5.1 months for erlotinib and chemotherapy, respectively, while the OS was reversed at 24.68 months for erlotinib and 26.16 months for chemotherapy. The chemotherapy arm gained 0.13 QALYs compared with erlotinib monotherapy (1.17 QALYs vs 1.04 QALYs), while erlotinib had lower costs ($55 230 vs $77 669), resulting in an ICER of $174 808 per QALY for the chemotherapy arm, which exceeds three times the Chinese GDP per capita. The most influential factors were the health utility of PFS, the cost of erlotinib and the health utility of progressed disease. Conclusion Erlotinib monotherapy may be acceptable as a cost-effective first-line treatment for NSCLC compared with gemcitabine-based chemotherapy. The results were robust to changes in assumptions. Trial registration number NCT01342965 and CTONG-0802. PMID:29654023

Synergistic growth inhibition of squamous cell carcinoma of the head and neck by erlotinib and epigallocatechin-3-gallate: the role of p53-dependent inhibition of nuclear factor-kappaB.

PubMed

Amin, A R M Ruhul; Khuri, Fadlo R; Chen, Zhuo Georgia; Shin, Dong M

2009-06-01

We have previously reported that the green tea polyphenol epigallocatechin-3-gallate (EGCG) and the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib had synergistic growth-inhibitory effects in cell culture and a nude mouse xenograft model of squamous cell carcinoma of the head and neck. However, the mechanism of their antitumor synergism is not fully understood. In the current study, we investigate the mechanism of their synergistic growth-inhibitory effects. The treatment of squamous cell carcinoma of the head and neck cell lines with erlotinib time-dependently increased the expression of cell cycle regulatory proteins p21 and p27 and apoptosis regulatory protein Bim. EGCG alone had very little or no effect on the expression of these proteins among the cell lines. However, simultaneous treatment with EGCG and erlotinib strongly inhibited erlotinib-induced expression of p21 and p27 without affecting the expression of Bim. Moreover, erlotinib increased the expression of p53 protein, the ablation of which by short hairpin RNA strongly inhibited EGCG- and erlotinib-mediated growth inhibition and the expression of p21, p27, and Bim. In addition, combined treatment with erlotinib and EGCG inhibited the protein level of p65 subunit of nuclear factor-kappaB and its transcriptional target Bcl-2, but failed to do so in cells with ablated p53. Taken together, our results, for the first time, suggest that erlotinib treatment activates p53, which plays a critical role in synergistic growth inhibition by erlotinib and EGCG via inhibiting nuclear factor-kappaB signaling pathway. Characterizing the underlying mechanisms of EGCG and erlotinib synergism will provide an important rationale for chemoprevention or treatment trials using this combination.

Comparison of effectiveness and adverse effects of gefitinib, erlotinib and icotinib among patients with non-small cell lung cancer: A network meta-analysis.

PubMed

Liu, Yuanyuan; Zhang, Yu; Feng, Gangling; Niu, Qiang; Xu, Shangzhi; Yan, Yizhong; Li, Shugang; Jing, Mingxia

2017-11-01

The present network meta-analysis aimed to compare the effectiveness and adverse effects of gefitinib, erlotinib and icotinib in the treatment of patients with non-small cell lung cancer (NSCLC). Two reviewers searched the Cochrane, PubMed, Embase, ScienceDirect, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals and Wanfang databases for relevant studies. Studies were then screened and evaluated, and data was extracted. End-points evaluated for NSCLC included complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), median survival time (MST) and adverse effects, including rash, diarrhea, nausea and vomiting, fatigue and abnormal liver function. For the analysis of incorporated studies, RevMan, SPSS, R and Stata software were used. A total of 43 studies with 7,168 patients were included in the network meta-analysis. No significant differences were observed in CR, PR, SD, PD, ORR or DCR between gefitinib, erlotinib and icotinib by using network meta analysis. Compared with gefitinib, erlotinib resulted in a higher rate of nausea and vomiting [adjusted odds ratio (OR)=2.0; 95% credible interval, 1.1-3.7]. However, no significant differences were observed in the rates of rash, diarrhea, fatigue or abnormal liver function using network meta-analysis. Compared with erlotinib, gefitinib resulted in a lower SD rate [OR=0.86; 95% confidence interval (CI): 0.75-0.99; P=0.04], and lower rates of rash (OR=0.45; 95% CI, 0.36-0.55; P<0.00001), diarrhea (OR=0.75; 95% CI, 0.61-0.92; P=0.005), nausea and vomiting (OR=0.47; 95% CI, 0.27-0.84; P=0.01) and fatigue (OR=0.43; 95% CI, 0.24-0.76; P=0.004) through meta-analysis of two congruent drugs. However, gefitinib resulted in a higher rate of rash compared with icotinib (OR=1.57; 95% CI, 1.18-2.09; P=0.002). Otherwise, no significant differences were observed in CR, PR

Comparison of effectiveness and adverse effects of gefitinib, erlotinib and icotinib among patients with non-small cell lung cancer: A network meta-analysis

PubMed Central

Liu, Yuanyuan; Zhang, Yu; Feng, Gangling; Niu, Qiang; Xu, Shangzhi; Yan, Yizhong; Li, Shugang; Jing, Mingxia

2017-01-01

The present network meta-analysis aimed to compare the effectiveness and adverse effects of gefitinib, erlotinib and icotinib in the treatment of patients with non-small cell lung cancer (NSCLC). Two reviewers searched the Cochrane, PubMed, Embase, ScienceDirect, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodicals and Wanfang databases for relevant studies. Studies were then screened and evaluated, and data was extracted. End-points evaluated for NSCLC included complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), median survival time (MST) and adverse effects, including rash, diarrhea, nausea and vomiting, fatigue and abnormal liver function. For the analysis of incorporated studies, RevMan, SPSS, R and Stata software were used. A total of 43 studies with 7,168 patients were included in the network meta-analysis. No significant differences were observed in CR, PR, SD, PD, ORR or DCR between gefitinib, erlotinib and icotinib by using network meta analysis. Compared with gefitinib, erlotinib resulted in a higher rate of nausea and vomiting [adjusted odds ratio (OR)=2.0; 95% credible interval, 1.1–3.7]. However, no significant differences were observed in the rates of rash, diarrhea, fatigue or abnormal liver function using network meta-analysis. Compared with erlotinib, gefitinib resulted in a lower SD rate [OR=0.86; 95% confidence interval (CI): 0.75–0.99; P=0.04], and lower rates of rash (OR=0.45; 95% CI, 0.36–0.55; P<0.00001), diarrhea (OR=0.75; 95% CI, 0.61–0.92; P=0.005), nausea and vomiting (OR=0.47; 95% CI, 0.27–0.84; P=0.01) and fatigue (OR=0.43; 95% CI, 0.24–0.76; P=0.004) through meta-analysis of two congruent drugs. However, gefitinib resulted in a higher rate of rash compared with icotinib (OR=1.57; 95% CI, 1.18–2.09; P=0.002). Otherwise, no significant differences were

CIPROFLOXACIN RESISTANCE PATTERN AMONG BACTERIA ISOLATED FROM PATIENTS WITH COMMUNITY-ACQUIRED URINARY TRACT INFECTION

PubMed Central

REIS, Ana Carolina Costa; SANTOS, Susana Regia da Silva; de SOUZA, Siane Campos; SALDANHA, Milena Góes; PITANGA, Thassila Nogueira; OLIVEIRA, Ricardo Riccio

2016-01-01

SUMMARY Objective: To identify the main bacterial species associated with community-acquired urinary tract infection (UTI) and to assess the pattern of ciprofloxacin susceptibility among bacteria isolated from urine cultures. Methods: We conducted a retrospective study in all the patients with community-acquired UTI seen in Santa Helena Laboratory, Camaçari, Bahia, Brazil during five years (2010-2014). All individuals who had a positive urine culture result were included in this study. Results: A total of 1,641 individuals met the inclusion criteria. Despite the fact that participants were female, we observed a higher rate of resistance to ciprofloxacin in males. The most frequent pathogens identified in urine samples were Escherichia coli, Klebsiella pneumoniae and Staphylococcus saprophyticus. Antimicrobial resistance has been observed mainly for ampicillin, sulfamethoxazole + trimethoprim and ciprofloxacin. Moreover, E. coli has shown the highest rate of ciprofloxacin resistance, reaching 36% of ciprofloxacin resistant strains in 2014. Conclusion: The rate of bacterial resistance to ciprofloxacin observed in the studied population is much higher than expected, prompting the need for rational use of this antibiotic, especially in infections caused by E. coli. Prevention of bacterial resistance can be performed through control measures to limit the spread of resistant microorganisms and a rational use of antimicrobial policy. PMID:27410913

Characterization of in vivo-acquired resistance to macrolides of Mycoplasma gallisepticum strains isolated from poultry

PubMed Central

2011-01-01

The macrolide class of antibiotics, including tylosin and tilmicosin, is widely used in the veterinary field for prophylaxis and treatment of mycoplasmosis. In vitro susceptibility testing of 50 strains of M. gallisepticum isolated in Israel during the period 1997-2010 revealed that acquired resistance to tylosin as well as to tilmicosin was present in 50% of them. Moreover, 72% (13/18) of the strains isolated from clinical samples since 2006 showed acquired resistance to enrofloxacin, tylosin and tilmicosin. Molecular typing of the field isolates, performed by gene-target sequencing (GTS), detected 13 molecular types (I-XIII). Type II was the predominant type prior to 2006 whereas type X, first detected in 2008, is currently prevalent. All ten type X strains were resistant to both fluoroquinolones and macrolides, suggesting selective pressure leading to clonal dissemination of resistance. However, this was not a unique event since resistant strains with other GTS molecular types were also found. Concurrently, the molecular basis for macrolide resistance in M. gallisepticum was identified. Our results revealed a clear-cut correlation between single point mutations A2058G or A2059G in domain V of the gene encoding 23S rRNA (rrnA, MGA_01) and acquired macrolide resistance in M. gallisepticum. Indeed, all isolates with MIC ≥ 0.63 μg/mL to tylosin and with MIC ≥ 1.25 μg/mL to tilmicosin possess one of these mutations, suggesting an essential role in decreased susceptibility of M. gallisepticum to 16-membered macrolides. PMID:21810258

Circulating heregulin level is associated with the efficacy of patritumab combined with erlotinib in patients with non-small cell lung cancer.

PubMed

Yonesaka, Kimio; Hirotani, Kenji; von Pawel, Joachim; Dediu, Mircea; Chen, Shuquan; Copigneaux, Catherine; Nakagawa, Kazuhiko

2017-03-01

Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n=212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib. Serum was obtained from participants prior to treatment (n=202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed. sHRG level was various (-1346-11,772pg/mL). Participants were divided into the sHRG-high or -low subgroups at the concentration defining near the third quartile, 980pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n=46, hazard ratio 0.42 [0.19-0.96], p=0.0327). In contrast, the HRG-low subgroup (n=148) had no improvement in PFS with patritumab. sHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Toxic shock syndrome due to community-acquired methicillin-resistant Staphylococcus aureus infection: Two case reports and a literature review in Japan.

PubMed

Sada, Ryuichi; Fukuda, Saori; Ishimaru, Hiroyasu

2017-01-01

Community-acquired methicillin-resistant Staphylococcus aureus has been spreading worldwide, including in Japan. However, few cases of toxic shock syndrome caused by Community-acquired methicillin-resistant Staphylococcus aureus have been reported in Japan. We report 2 cases, in middle-aged women, of toxic shock syndrome due to Community-acquired methicillin-resistant Staphylococcus aureus via a vaginal portal of entry. The first patient had used a tampon and the second patient had vaginitis due to a cleft narrowing associated with vulvar lichen sclerosus. Both patients were admitted to our hospital with septic shock and severe acute kidney injury and subsequently recovered with appropriate antibiotic treatment. In our review of the literature, 8 cases of toxic shock syndrome caused by Community-acquired methicillin-resistant Staphylococcus aureus were reported in Japan. In these 8 cases, the main portals of entry were the skin and respiratory tract; however, the portal of entry of Community-acquired methicillin-resistant Staphylococcus aureus from a vaginal lesion has not been reported in Japan previously.

Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis: Secondary Analysis of a Randomized Clinical Trial.

PubMed

Samadder, N Jewel; Kuwada, Scott K; Boucher, Kenneth M; Byrne, Kathryn; Kanth, Priyanka; Samowitz, Wade; Jones, David; Tavtigian, Sean V; Westover, Michelle; Berry, Therese; Jasperson, Kory; Pappas, Lisa; Smith, Laurel; Sample, Danielle; Burt, Randall W; Neklason, Deborah W

2018-02-08

Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months. The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009). In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. clinicaltrials.gov Identifier: NCT01187901.

Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

PubMed

Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

2012-12-01

Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations.

PubMed

Intlekofer, Andrew M; Shih, Alan H; Wang, Bo; Nazir, Abbas; Rustenburg, Ariën S; Albanese, Steven K; Patel, Minal; Famulare, Christopher; Correa, Fabian M; Takemoto, Naofumi; Durani, Vidushi; Liu, Hui; Taylor, Justin; Farnoud, Noushin; Papaemmanuil, Elli; Cross, Justin R; Tallman, Martin S; Arcila, Maria E; Roshal, Mikhail; Petsko, Gregory A; Wu, Bin; Choe, Sung; Konteatis, Zenon D; Biller, Scott A; Chodera, John D; Thompson, Craig B; Levine, Ross L; Stein, Eytan M

2018-06-27

Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG) 1-8 . Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants 9,10 . In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML 11 . Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies.

Community-acquired methicillin-resistant Staphylococcus aureus: community transmission, pathogenesis, and drug resistance.

PubMed

Yamamoto, Tatsuo; Nishiyama, Akihito; Takano, Tomomi; Yabe, Shizuka; Higuchi, Wataru; Razvina, Olga; Shi, Da

2010-08-01

Methicillin-resistant Staphylococcus aureus (MRSA) is able to persist not only in hospitals (with a high level of antimicrobial agent use) but also in the community (with a low level of antimicrobial agent use). The former is called hospital-acquired MRSA (HA-MRSA) and the latter community-acquired MRSA (CA-MRSA). It is believed MRSA clones are generated from S. aureus through insertion of the staphylococcal cassette chromosome mec (SCCmec), and outbreaks occur as they spread. Several worldwide and regional clones have been identified, and their epidemiological, clinical, and genetic characteristics have been described. CA-MRSA is likely able to survive in the community because of suitable SCCmec types (type IV or V), a clone-specific colonization/infection nature, toxin profiles (including Pantone-Valentine leucocidin, PVL), and narrow drug resistance patterns. CA-MRSA infections are generally seen in healthy children or young athletes, with unexpected cases of diseases, and also in elderly inpatients, occasionally surprising clinicians used to HA-MRSA infections. CA-MRSA spreads within families and close-contact groups or even through public transport, demonstrating transmission cores. Re-infection (including multifocal infection) frequently occurs, if the cores are not sought out and properly eradicated. Recently, attention has been given to CA-MRSA (USA300), which originated in the US, and is growing as HA-MRSA and also as a worldwide clone. CA-MRSA infection in influenza season has increasingly been noted as well. MRSA is also found in farm and companion animals, and has occasionally transferred to humans. As such, the epidemiological, clinical, and genetic behavior of CA-MRSA, a growing threat, is focused on in this study.

Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: a case report and review of the literature.

PubMed

Togashi, Yosuke; Masago, Katsuhiro; Hamatani, Yasuhiro; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Mishima, Michiaki

2012-08-01

The most serious adverse reaction associated with treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is drug-induced interstitial lung disease (ILD). Because EGFR-TKIs are key drugs for patients with non-small cell lung cancer who have somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations), several cases of retreatment with EGFR-TKIs after ILD induced by these drugs have been reported. Here, we present a 68-year-old man with lung adenocarcinoma and leptomeningeal metastases having an EGFR mutation who was retreated with erlotinib after erlotinib-induced ILD. He suffered no ILD recurrence and his leptomeningeal metastases dramatically improved. In addition to the present case, reports of nine patients who were retreated with EGFR-TKIs after ILD were found in the literature. Only one patient had recurrence of ILD (although seven were retreated at a reduced dose of EGFR-TKIs, including the patient with recurrence). In contrast, three patients had no recurrence of ILD even without dose-reduction. These reports suggest that dose-reduction plays a limited role in preventing recurrence. Many patients received corticosteroids during retreatment, but not the one with recurrence of ILD. This may suggest that corticosteroids can prevent recurrence due to their antiinflammatory properties. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Acquired drug resistance conferred by a KRAS gene mutation following the administration of cetuximab: a case report

PubMed Central

2013-01-01

Background Although a number of studies have reported acquired drug resistance due to administration of epidermal growth factor receptor antibody inhibitors, the underlying causes of this phenomenon remain unclear. Case presentation Here we report a case of a 75-year-old man with liver metastasis at 3 years after a successful transverse colectomy to treat KRAS wild-type colorectal cancer. While initial administration of epidermal growth factor receptor inhibitors proved effective, continued use of the same treatment resulted in new peritoneal seeding. An acquired KRAS mutation was found in a resected tissue specimen from one such area. This mutation, possibly caused by administration of epidermal growth factor receptor inhibitors, appears to have conferred drug resistance. Conclusion The present findings suggest that administration of epidermal growth factor receptor inhibitors results in an acquired KRAS mutation that confers drug resistance. PMID:24304820

Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.

PubMed

Hwang, Ki-Eun; Kwon, Su-Jin; Kim, Young-Suk; Park, Do-Sim; Kim, Byoung-Ryun; Yoon, Kwon-Ha; Jeong, Eun-Taik; Kim, Hak-Ryul

2014-05-01

Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of β-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-β-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-β-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib-simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/β-catenin signaling-dependent down-regulation of survivin and apoptosis induction. Copyright © 2014 Elsevier Inc. All rights reserved.

Next-generation systemic acquired resistance.

PubMed

Luna, Estrella; Bruce, Toby J A; Roberts, Michael R; Flors, Victor; Ton, Jurriaan

2012-02-01

Systemic acquired resistance (SAR) is a plant immune response to pathogen attack. Recent evidence suggests that plant immunity involves regulation by chromatin remodeling and DNA methylation. We investigated whether SAR can be inherited epigenetically following disease pressure by Pseudomonas syringae pv tomato DC3000 (PstDC3000). Compared to progeny from control-treated Arabidopsis (Arabidopsis thaliana; C(1)), progeny from PstDC3000-inoculated Arabidopsis (P(1)) were primed to activate salicylic acid (SA)-inducible defense genes and were more resistant to the (hemi)biotrophic pathogens Hyaloperonospora arabidopsidis and PstDC3000. This transgenerational SAR was sustained over one stress-free generation, indicating an epigenetic basis of the phenomenon. Furthermore, P(1) progeny displayed reduced responsiveness of jasmonic acid (JA)-inducible genes and enhanced susceptibility to the necrotrophic fungus Alternaria brassicicola. This shift in SA- and JA-dependent gene responsiveness was not associated with changes in corresponding hormone levels. Instead, chromatin immunoprecipitation analyses revealed that SA-inducible promoters of PATHOGENESIS-RELATED GENE1, WRKY6, and WRKY53 in P(1) plants are enriched with acetylated histone H3 at lysine 9, a chromatin mark associated with a permissive state of transcription. Conversely, the JA-inducible promoter of PLANT DEFENSIN1.2 showed increased H3 triple methylation at lysine 27, a mark related to repressed gene transcription. P(1) progeny from the defense regulatory mutant non expressor of PR1 (npr1)-1 failed to develop transgenerational defense phenotypes, demonstrating a critical role for NPR1 in expression of transgenerational SAR. Furthermore, the drm1drm2cmt3 mutant that is affected in non-CpG DNA methylation mimicked the transgenerational SAR phenotype. Since PstDC3000 induces DNA hypomethylation in Arabidopsis, our results suggest that transgenerational SAR is transmitted by hypomethylated genes that direct priming

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.

PubMed

Misale, Sandra; Yaeger, Rona; Hobor, Sebastijan; Scala, Elisa; Janakiraman, Manickam; Liska, David; Valtorta, Emanuele; Schiavo, Roberta; Buscarino, Michela; Siravegna, Giulia; Bencardino, Katia; Cercek, Andrea; Chen, Chin-Tung; Veronese, Silvio; Zanon, Carlo; Sartore-Bianchi, Andrea; Gambacorta, Marcello; Gallicchio, Margherita; Vakiani, Efsevia; Boscaro, Valentina; Medico, Enzo; Weiser, Martin; Siena, Salvatore; Di Nicolantonio, Federica; Solit, David; Bardelli, Alberto

2012-06-28

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

Erlotinib-Conjugated Iron Oxide Nanoparticles as a Smart Cancer-Targeted Theranostic Probe for MRI.

PubMed

Ali, Ahmed Atef Ahmed; Hsu, Fei-Ting; Hsieh, Chia-Ling; Shiau, Chia-Yang; Chiang, Chiao-Hsi; Wei, Zung-Hang; Chen, Cheng-Yu; Huang, Hsu-Shan

2016-11-11

We designed and synthesized novel theranostic nanoparticles that showed the considerable potential for clinical use in targeted therapy, and non-invasive real-time monitoring of tumors by MRI. Our nanoparticles were ultra-small with superparamagnetic iron oxide cores, conjugated to erlotinib (FeDC-E NPs). Such smart targeted nanoparticles have the preference to release the drug intracellularly rather than into the bloodstream, and specifically recognize and kill cancer cells that overexpress EGFR while being non-toxic to EGFR-negative cells. MRI, transmission electron microscopy and Prussian blue staining results indicated that cellular uptake and intracellular accumulation of FeDC-E NPs in the EGFR overexpressing cells was significantly higher than those of the non-erlotinib-conjugated nanoparticles. FeDC-E NPs inhibited the EGFR-ERK-NF-κB signaling pathways, and subsequently suppressed the migration and invasion capabilities of the highly invasive and migrative CL1-5-F4 cancer cells. In vivo tumor xenograft experiments using BALB/c nude mice showed that FeDC-E NPs could effectively inhibit the growth of tumors. T 2 -weighted MRI images of the mice showed significant decrease in the normalized signal within the tumor post-treatment with FeDC-E NPs compared to the non-targeted control iron oxide nanoparticles. This is the first study to use erlotinib as a small-molecule targeting agent for nanoparticles.

Erlotinib-Conjugated Iron Oxide Nanoparticles as a Smart Cancer-Targeted Theranostic Probe for MRI

NASA Astrophysics Data System (ADS)

Ali, Ahmed Atef Ahmed; Hsu, Fei-Ting; Hsieh, Chia-Ling; Shiau, Chia-Yang; Chiang, Chiao-Hsi; Wei, Zung-Hang; Chen, Cheng-Yu; Huang, Hsu-Shan

2016-11-01

We designed and synthesized novel theranostic nanoparticles that showed the considerable potential for clinical use in targeted therapy, and non-invasive real-time monitoring of tumors by MRI. Our nanoparticles were ultra-small with superparamagnetic iron oxide cores, conjugated to erlotinib (FeDC-E NPs). Such smart targeted nanoparticles have the preference to release the drug intracellularly rather than into the bloodstream, and specifically recognize and kill cancer cells that overexpress EGFR while being non-toxic to EGFR-negative cells. MRI, transmission electron microscopy and Prussian blue staining results indicated that cellular uptake and intracellular accumulation of FeDC-E NPs in the EGFR overexpressing cells was significantly higher than those of the non-erlotinib-conjugated nanoparticles. FeDC-E NPs inhibited the EGFR-ERK-NF-κB signaling pathways, and subsequently suppressed the migration and invasion capabilities of the highly invasive and migrative CL1-5-F4 cancer cells. In vivo tumor xenograft experiments using BALB/c nude mice showed that FeDC-E NPs could effectively inhibit the growth of tumors. T2-weighted MRI images of the mice showed significant decrease in the normalized signal within the tumor post-treatment with FeDC-E NPs compared to the non-targeted control iron oxide nanoparticles. This is the first study to use erlotinib as a small-molecule targeting agent for nanoparticles.

Erlotinib or best supportive care for third-line treatment of advanced non-small-cell lung cancer: a real-world cost-effectiveness analysis.

PubMed

Cromwell, Ian; van der Hoek, Kimberly; Malfair Taylor, Suzanne C; Melosky, Barbara; Peacock, Stuart

2012-06-01

Erlotinib has been approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC) in British Columbia (BC). A cost-effectiveness analysis was conducted to compare costs and effectiveness in patients who received third-line erlotinib to those in a historical patient cohort that would have been eligible had erlotinib been available. In a population of patients who have been treated with drugs for advanced NSCLC, overall survival (OS), progression-to-death survival (PTD) and probability of survival one year after end of second-line (1YS) were determined using a Kaplan-Meier survival analysis. Costs were collected retrospectively from the perspective of the BC health care system. Incremental mean OS was 90 days (0.25 LYG), and incremental mean cost was $11,102 (CDN 2009), resulting in a mean ICER of $36,838/LYG. Univariate sensitivity analysis yielded ICERs ranging from $21,300 to $51,700/LYG. Our analysis suggests that erlotinib may be an effective and cost-effective third-line treatment for advanced NSCLC compared to best supportive care. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma.

PubMed

Kuczynski, Elizabeth A; Yin, Melissa; Bar-Zion, Avinoam; Lee, Christina R; Butz, Henriett; Man, Shan; Daley, Frances; Vermeulen, Peter B; Yousef, George M; Foster, F Stuart; Reynolds, Andrew R; Kerbel, Robert S

2016-08-01

The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents. To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology. While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option. This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling. © The Author 2016. Published by

Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae.

PubMed

Ewig, S; Ruiz, M; Torres, A; Marco, F; Martinez, J A; Sanchez, M; Mensa, J

1999-06-01

The aim of the study was to determine the incidence of and risk factors for drug resistance of Streptococcus pneumoniae, and its impact on the outcome among hospitalized patients of pneumococcal pneumonia acquired in the community. Consecutive patients with culture-proven pneumococcal pneumonia were prospectively studied with regard to the incidence of pneumococcal drug resistance, potential risk factors, and in-hospital outcome variables. A total of 101 patients were studied. Drug resistance to penicillin, cephalosporin, or a macrolide drug was found in pneumococci from 52 of the 101 (52%) patients; 49% of these isolates were resistant to penicillin (16% intermediate resistance, 33% high resistance), 31% to cephalosporin (22% intermediate and 9% high resistance), and 27% to a macrolide drug. In immunocompetent patients, age > 65 yr was significantly associated with resistance to cephalosporin (odds ratio [OR]: 5.0; 95% confidence interval [CI]: 1.3 to 18.8, p = 0. 01), and with the presence of > 2 comorbidities with resistance to penicillin (OR: 4.7; 95% CI: 1.2 to 19.1; p < 0.05). In immunosuppressed patients, bacteremia was inversely associated with resistance to penicillin and cephalosporin (OR: 0.04; 95% CI: 0.003 to 0.45; p < 0.005; and OR: 0.46; 95% CI: 0.23 to 0.93; p < 0.05, respectively). Length of hospital stay, severity of pneumonia, and complications were not significantly affected by drug resistance. Mortality was 15% in patients with any drug resistance, as compared with 6% in those without resistance. However, any drug resistance was not significantly associated with death (relative risk [RR]: 2. 5; 95% CI: 0.7 to 8.9; p = 0.14). Moreover, attributable mortality in the presence of discordant antimicrobial treatment was 12%, as compared with 10% (RR: 1.2; 95% CI: 0.3 to 5.3; p = 0.67) in the absence of such treatment. We conclude that the incidence of drug-resistant pneumococci was high. Risk factors for drug resistance included advanced age

Antibacterial resistance patterns of pediatric community-acquired urinary infection: Overview.

PubMed

Konca, Capan; Tekin, Mehmet; Uckardes, Fatih; Akgun, Sadik; Almis, Habip; Bucak, Ibrahim Hakan; Genc, Yeliz; Turgut, Mehmet

2017-03-01

Urinary tract infection (UTI) is common in children. The aim of this study was therefor to construct a guide for the empirical antibiotic treatment of community-acquired UTI by investigating the etiology and antimicrobial resistance patterns of uropathogens and analyzing the epidemiological and clinical patient characteristics. A total of 158 children with positive urine culture were included in the study. Antibiotic susceptibility testing was performed with Vitek 2 Compact for 28 commonly used antimicrobials. Mean age was 3.36 ± 3.38 years (range, 45 days-15 years). Escherichia coli (60.1%), and Klebsiella spp. (16.5%) were the most common uropathogens. For all Gram-negative isolates, a high level of resistance was found against ampicillin/sulbactam (60.1%), trimethoprim/sulfamethoxazole (44.2%), cefazolin (36.2%), cefuroxime sodium (33.5%), and amoxicillin/clavulanate (31.5%). A low level of resistance was noted against cefepime (8.7%), ertapenem (4.6%), norfloxacin (1.3%), and meropenem (0.7%). There was no resistance against amikacin. There is high antibiotic resistance in children with UTI. The patterns of uropathogen antimicrobial resistance vary in susceptibility to antimicrobials depending on region and time. Thus, the trends of antibiotic susceptibility patterns should be analyzed periodically to select the appropriate regimen for UTI treatment. © 2016 Japan Pediatric Society.

Long-distance communication and signal amplification in systemic acquired resistance

PubMed Central

Shah, Jyoti; Zeier, Jürgen

2013-01-01

Systemic acquired resistance (SAR) is an inducible defense mechanism in plants that confers enhanced resistance against a variety of pathogens. SAR is activated in the uninfected systemic (distal) organs in response to a prior (primary) infection elsewhere in the plant. SAR is associated with the activation of salicylic acid (SA) signaling and the priming of defense responses for robust activation in response to subsequent infections. The activation of SAR requires communication by the primary infected tissues with the distal organs. The vasculature functions as a conduit for the translocation of factors that facilitate long-distance intra-plant communication. In recent years, several metabolites putatively involved in long-distance signaling have been identified. These include the methyl ester of SA (MeSA), the abietane diterpenoid dehydroabietinal (DA), the dicarboxylic acid azelaic acid (AzA), and a glycerol-3-phosphate (G3P)-dependent factor. Long-distance signaling by some of these metabolites also requires the lipid-transfer protein DIR1 (DEFECTIVE IN INDUCED RESISTANCE 1). The relative contribution of these factors in long-distance signaling is likely influenced by environmental conditions, for example light. In the systemic leaves, the AGD2-LIKE DEFENSE RESPONSE PROTEIN1 (ALD1)-dependent production of the lysine catabolite pipecolic acid (Pip), FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1) signaling, as well as SA synthesis and downstream signaling are required for the activation of SAR. This review summarizes the involvement and interaction between long-distance SAR signals and details the recently discovered role of Pip in defense amplification and priming that allows plants to acquire immunity at the systemic level. Recent advances in SA signaling and perception are also highlighted. PMID:23440336

Cost-effectiveness of first-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy

PubMed Central

Khan, Iftekhar; Morris, Stephen; Hackshaw, Allan; Lee, Siow-Ming

2015-01-01

Objective To assess the cost-effectiveness of erlotinib versus supportive care (placebo) overall and within a predefined rash subgroup in elderly patients with advanced non-small-cell lung cancer who are unfit for chemotherapy and receive only active supportive care due to their poor performance status or presence of comorbidities. Setting Between 2005 and 2009, a total of 670 patients with non-small cell lung cancer (NSCLC) were randomised across 78 hospital sites (centres) in the UK. Participants 670 patients with pathologically confirmed stage IIIb-IV NSCLC, unfit for chemotherapy, predominantly poor performance status (>2 on Eastern Cooperative Oncology Group, ECOG) and estimated life expectancy of at least 8 weeks. Patients were followed until disease progression or death, including a subgroup of patients who developed first cycle rash. Interventions Patients were randomised (1:1) to receive best supportive care plus oral placebo or erlotinib (150 mg/day) until disease progression, toxicity or death. Primary outcome Overall survival (OS). Secondary outcomes Progression-free survival (PFS), tumour response and quality adjusted life years (QALY), including within prespecified subgroups. Results The mean incremental cost per QALY in all patients was £202 571/QALY. The probability of cost-effectiveness of erlotinib in all patients was <10% at thresholds up to £100 000. However, within the rash subgroup, the incremental cost/QALY was £56 770/QALY with a probability of cost-effectiveness of about 80% for cost-effectiveness thresholds between £50 000 to £60 000. Conclusions Erlotinib has about 80% chance of being cost-effective at thresholds between £50 000–£60 000 in a subset of elderly poor performance patients with NSCLC unfit for chemotherapy who develop first cycle (28 days) rash. Erlotinib is potentially cost-effective for this population, for which few treatment options apart from best supportive care are available. Trial

Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib.

PubMed

Acquaviva, Jaime; Smith, Donald L; Jimenez, John-Paul; Zhang, Chaohua; Sequeira, Manuel; He, Suqin; Sang, Jim; Bates, Richard C; Proia, David A

2014-02-01

Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF(V600E) inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF(V600E) mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF(V600E) provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF(V600E) by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF(V600E)-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors.

Acquired antibiotic resistance among wild animals: the case of Iberian Lynx (Lynx pardinus).

PubMed

Sousa, Margarida; Gonçalves, Alexandre; Silva, Nuno; Serra, Rodrigo; Alcaide, Eva; Zorrilla, Irene; Torres, Carmen; Caniça, Manuela; Igrejas, Gilberto; Poeta, Patrícia

2014-01-01

The selective pressure generated by the clinical misuse of antibiotics has been the major driving force leading to the emergence of antibiotic resistance among bacteria. Antibiotics or even resistant bacteria are released into the environment and contaminate the surrounding areas. Human and animal populations in contact with these sources are able to become reservoirs of these resistant organisms. Then, due to the convergence between habitats, the contact of wild animals with other animals, humans, or human sources is now more common and this leads to an increase in the exchange of resistance determinants between their microbiota. Indeed, it seems that wildlife populations living in closer proximity to humans have higher levels of antibiotic resistance. Now, the Iberian Lynx (Lynx pardinus) is a part of this issue, being suggested as natural reservoir of acquired resistant bacteria. The emerging public health concern regarding microbial resistance to antibiotics is becoming true: the bacteria are evolving and are now affecting unintentional hosts.

Antimicrobial resistance among Escherichia coli that cause childhood community-acquired urinary tract infections in Northern Italy.

PubMed

Caracciolo, Alessandra; Bettinelli, Alberto; Bonato, Claudio; Isimbaldi, Clementina; Tagliabue, Alessandro; Longoni, Laura; Bianchetti, Mario G

2011-01-06

Resistance rate of Escherichia coli against antimicrobials that are commonly prescribed in pediatric urinary tract infections is currently a matter of concern. The antimicrobial susceptibility patterns of uropathogenic Escherichia coli strains to the common antibimcrobials ampicillin, cotrimoxazole, coamoxyclav, ceftazidime, ceftriaxone, nitrofurantoin, and gentamycin were determined in 177 children aged from 2 to 36 months. They presented with their first symptomatic community acquired urinary tract infection at the Department of Pediatrics, San Leopoldo Mandic Hospital, Merate-Lecco. High rates of ampicillin (inpatients: 50%; outpatients: 52%) resistance were identified. The resistance for cotrimoxazole (inpatients: 22%; outpatients: 15%) and especially coamoxyclav (inpatients: 6%; outpatients: 10%) was less pronounced than that to ampicillin. No resistance or less than 1% of resistance was identified for ceftazidime, ceftriaxone, nitrofurantoin, and gentamycin both in inpatients and in outpatients. Italian children affected with a community acquired urinary tract infection are initially managed orally with coamoxyclav or parenterally with ceftriaxone. The results of the present retrospective analysis support this attitude. Parenteral ceftriaxone or an aminoglycoside should be considered for patients on antimicrobial prophylaxis or recently prescribed antimicrobials.

Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer.

PubMed

Wu, Shi-Xiu; Wang, Lv-Hua; Luo, Hong-Lei; Xie, Cong-Ying; Zhang, Xue-Bang; Hu, Wei; Zheng, An-Ping; Li, Duo-Jie; Zhang, Hong-Yan; Xie, Cong-Hua; Lian, Xi-Long; Du, De-Xi; Chen, Ming; Bian, Xiu-Hua; Tan, Bang-Xian; Jiang, Hao; Zhang, Hong-Bo; Wang, Jian-Hua; Jing, Zhao; Xia, Bing; Zhang, Ni; Zhang, Ping; Li, Wen-Feng; Zhao, Fu-Jun; Tian, Zhi-Feng; Liu, Hui; Huang, Ke-Wei; Hu, Jin; Xie, Rui-Fei; Du, Lin; Li, Gang

2018-04-01

This randomised phase III study was conducted to investigate the efficacy of extended nodal irradiation (ENI) and/or erlotinib in inoperable oesophageal squamous cell cancer (ESCC). Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to one of four treatment groups: group A, radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel 135 mg/m 2  day 1 and cisplatin 20 mg/m 2 days 1-3, every 4 weeks) plus erlotinib (150 mg per day during chemoradiotherapy); group B, radiotherapy adoption of ENI with two cycles of concurrent TP; group C, radiotherapy adoption of conventional field irradiation (CFI) with two cycles of concurrent TP plus erlotinib; group D, radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 352 patients (88 assigned to each treatment group) were enrolled. The 2-year overall survival rates of group A, B, C and D were 57.8%, 49.9%, 44.9% and 38.7%, respectively (P = 0.015). Group A significantly improved 2-year overall survival compared with group D. The ENI significantly improved overall survival in patients with inoperable ESCC (P = 0.014). The addition of erlotinib significantly decreased loco-regional recurrence (P = 0.042). Aside from rash and radiation oesophagitis, the incidence of grade 3 or greater toxicities did not differ among 4 groups. Chemoradiotherapy with ENI and erlotinib might represent a substantial improvement on the standard of care for inoperable ESCC. ENI alone should be adopted in concurrent chemoradiotherapy for ESCC patients. Copyright © 2018 Elsevier Ltd. All rights reserved.

Early 18F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

PubMed

De Rosa, Viviana; Iommelli, Francesca; Monti, Marcello; Mainolfi, Ciro Gabriele; Fonti, Rosa; Del Vecchio, Silvana

2016-12-01

The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake in animal models bearing erlotinib-resistant NSCLC may have different imaging patterns of response to erlotinib depending on the molecular mechanisms underlying resistance. Animal tumor models were developed using NSCLC H1975 cells bearing the T790M mutation and H1993 cells with MET amplification. Nude mice bearing erlotinib-resistant H1975 and H1993 xenografts (four animals for each cell line and for each treatment) were subjected to 18 F-FDG PET/CT scan before and immediately after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib, or vehicle. A three-dimensional region of interest analysis was performed to determine the percent change of 18 F-FDG uptake in response to treatment. At the end of the imaging studies, tumors were removed and analyzed for glycolytic and mitochondrial proteins as well as levels of cyclin D1. Imaging studies with 18 F-FDG PET/CT in H1975 tumor-bearing mice showed a reduction of 18 F-FDG uptake of 25.87 % ± 8.93 % after treatment with WZ4002 whereas an increase of 18 F-FDG uptake up to 23.51 % ± 9.72 % was observed after treatment with erlotinib or vehicle. Conversely, H1993 tumors showed a reduction of 18 F-FDG uptake after treatment with both crizotinib (14.70 % ± 1.30 %) and erlotinib (18.40 % ± 9.19 %) and an increase of tracer uptake in vehicle-treated (56.65 % ± 5.65 %) animals. The in vivo reduction of 18 F-FDG uptake was always associated with downregulation of HKII and p-PKM2 Tyr105 glycolytic proteins and upregulation of mitochondrial complexes (subunits I-IV) in excised tumors. 18 F-FDG uptake is a reliable imaging biomarker of T790M

Proteomic analysis of acquired tamoxifen resistance in MCF-7 cells reveals expression signatures associated with enhanced migration

PubMed Central

2012-01-01

Introduction Acquired tamoxifen resistance involves complex signaling events that are not yet fully understood. Successful therapeutic intervention to delay the onset of hormone resistance depends critically on mechanistic elucidation of viable molecular targets associated with hormone resistance. This study was undertaken to investigate the global proteomic alterations in a tamoxifen resistant MCF-7 breast cancer cell line obtained by long term treatment of the wild type MCF-7 cell line with 4-hydroxytamoxifen (4-OH Tam). Methods We cultured MCF-7 cells with 4-OH Tam over a period of 12 months to obtain the resistant cell line. A gel-free, quantitative proteomic method was used to identify and quantify the proteome of the resistant cell line. Nano-flow high-performance liquid chromatography coupled to high resolution Fourier transform mass spectrometry was used to analyze fractionated peptide mixtures that were isobarically labeled from the resistant and control cell lysates. Real time quantitative PCR and Western blots were used to verify selected proteomic changes. Lentiviral vector transduction was used to generate MCF-7 cells stably expressing S100P. Online pathway analysis was performed to assess proteomic signatures in tamoxifen resistance. Survival analysis was done to evaluate clinical relevance of altered proteomic expressions. Results Quantitative proteomic analysis revealed a wide breadth of signaling events during transition to acquired tamoxifen resistance. A total of 629 proteins were found significantly changed with 364 up-regulated and 265 down-regulated. Collectively, these changes demonstrated the suppressed state of estrogen receptor (ER) and ER-regulated genes, activated survival signaling and increased migratory capacity of the resistant cell line. The protein S100P was found to play a critical role in conferring tamoxifen resistance and enhanced cell motility. Conclusions Our data demonstrate that the adaptive changes in the proteome of

Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial.

PubMed

Ramalingam, Suresh S; Jänne, Pasi A; Mok, Tony; O'Byrne, Kenneth; Boyer, Michael J; Von Pawel, Joachim; Pluzanski, Adam; Shtivelband, Mikhail; Docampo, Lara Iglesias; Bennouna, Jaafar; Zhang, Hui; Liang, Jane Q; Doherty, Jim P; Taylor, Ian; Mather, Cecile B; Goldberg, Zelanna; O'Connell, Joseph; Paz-Ares, Luis

2014-11-01

Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade

Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

PubMed

Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

2014-02-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Silicon Phthalocyanines Axially Disubstituted with Erlotinib toward Small-Molecular-Target-Based Photodynamic Therapy.

PubMed

Chen, Juan-Juan; Huang, Yi-Zhen; Song, Mei-Ru; Zhang, Zhi-Hong; Xue, Jin-Ping

2017-09-21

Small-molecular-target-based photodynamic therapy-a promising targeted anticancer strategy-was developed by conjugating zinc(II) phthalocyanine with a small-molecular-target-based anticancer drug. To prevent self-aggregation and avoid problems of phthalocyanine isomerization, two silicon phthalocyanines di-substituted axially with erlotinib have been synthesized and fully characterized. These conjugates are present in monomeric form in various solvents as well as culture media. Cell-based experiments showed that these conjugates localize in lysosomes and mitochondria, while maintaining high photodynamic activities (IC 50 values as low as 8 nm under a light dose of 1.5 J cm -2 ). With erlotinib as the targeting moiety, two conjugates were found to exhibit high specificity for EGFR-overexpressing cancer cells. Various poly(ethylene glycol) (PEG) linker lengths were shown to have an effect on the photophysical/photochemical properties and on in vitro phototoxicity. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Primary and acquired resistance to biologic therapies in gastrointestinal cancers.

PubMed

Lubner, Sam J; Uboha, Nataliya V; Deming, Dustin A

2017-06-01

Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways.

Primary and acquired resistance to biologic therapies in gastrointestinal cancers

PubMed Central

Lubner, Sam J.; Uboha, Nataliya V.; Deming, Dustin A.

2017-01-01

Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways. PMID:28736637

Activation of EGFR Bypass Signaling by TGFα Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells.

PubMed

Tani, Tetsuo; Yasuda, Hiroyuki; Hamamoto, Junko; Kuroda, Aoi; Arai, Daisuke; Ishioka, Kota; Ohgino, Keiko; Miyawaki, Masayoshi; Kawada, Ichiro; Naoki, Katsuhiko; Hayashi, Yuichiro; Betsuyaku, Tomoko; Soejima, Kenzo

2016-01-01

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling. ©2015 American Association for Cancer Research.

A critical role for Arabidopsis MILDEW RESISTANCE LOCUS O2 in systemic acquired resistance.

PubMed

Gruner, Katrin; Zeier, Tatyana; Aretz, Christina; Zeier, Jürgen

2018-04-16

Members of the MILDEW RESISTANCE LOCUS O (MLO) gene family confer susceptibility to powdery mildews in different plant species, and their existence therefore seems to be disadvantageous for the plant. We recognized that expression of the Arabidopsis MLO2 gene is induced after inoculation with the bacterial pathogen Pseudomonas syringae, promoted by salicylic acid (SA) signaling, and systemically enhanced in the foliage of plants exhibiting systemic acquired resistance (SAR). Importantly, distinct mlo2 mutant lines were unable to systemically increase resistance to bacterial infection after inoculation with P. syringae, indicating that the function of MLO2 is necessary for biologically induced SAR in Arabidopsis. Our data also suggest that the close homolog MLO6 has a supportive but less critical role in SAR. In contrast to SAR, basal resistance to bacterial infection was not affected in mlo2. Remarkably, SAR-defective mlo2 mutants were still competent in systemically increasing the levels of the SAR-activating metabolites pipecolic acid (Pip) and SA after inoculation, and to enhance SAR-related gene expression in distal plant parts. Furthermore, although MLO2 was not required for SA- or Pip-inducible defense gene expression, it was essential for the proper induction of disease resistance by both SAR signals. We conclude that MLO2 acts as a critical downstream component in the execution of SAR to bacterial infection, being required for the translation of elevated defense responses into disease resistance. Moreover, our data suggest a function for MLO2 in the activation of plant defense priming during challenge by P. syringae. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

Erlotinib in African Americans with Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Study with Genetic and Pharmacokinetic Analysis

PubMed Central

Phelps, Mitch A.; Stinchcombe, Thomas E.; Blachly, James S.; Zhao, Weiqiang; Schaaf, Larry J.; Starrett, Sherri L.; Wei, Lai; Poi, Ming; Wang, Danxin; Papp, Audrey; Aimiuwu, Josephine; Gao, Yue; Li, Junan; Otterson, Gregory A.; Hicks, William J.; Socinski, Mark A.; Villalona-Calero, Miguel A.

2014-01-01

Prospective studies focusing on EGFR inhibitors in African Americans with NSCLC have not been previously performed. In this phase II randomized study, 55 African Americans with NSCLC received erlotinib 150mg/day or a body weight adjusted dose with subsequent escalations to the maximum allowable, 200mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower compared to previous reports, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics revealed only two EGFR mutations, EGFR amplification in 17/47 samples, 8 KRAS mutations and 5 EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Observed low incidence of toxicity and low erlotinib exposure suggest standardized and maximum allowable dosing may be suboptimal in African Americans. PMID:24781527

Gemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group.

PubMed

Irigoyen, Antonio; Gallego, Javier; Guillén Ponce, Carmen; Vera, Ruth; Iranzo, Vega; Ales, Inmaculada; Arévalo, Sara; Pisa, Aleydis; Martín, Marta; Salud, Antonieta; Falcó, Esther; Sáenz, Alberto; Manzano Mozo, José Luis; Pulido, Gema; Martínez Galán, Joaquina; Pazo-Cid, Roberto; Rivera, Fernando; García García, Teresa; Serra, Olbia; Fernández Parra, Eva Ma; Hurtado, Alicia; Gómez Reina, Ma José; López Gomez, Luis Jesús; Martínez Ortega, Esther; Benavides, Manuel; Aranda, Enrique

2017-04-01

Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC. Previously untreated mPC patients were randomised to receive G (1000 mg/m 2 , days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m 2 , days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety. 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014). PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

PubMed Central

Awad, Mark M.; Katayama, Ryohei; McTigue, Michele; Liu, Wei; Deng, Ya-Li; Brooun, Alexei; Friboulet, Luc; Huang, Donghui; Falk, Matthew D.; Timofeevski, Sergei; Wilner, Keith D.; Lockerman, Elizabeth L.; Khan, Tahsin M.; Mahmood, Sidra; Gainor, Justin F.; Digumarthy, Subba R.; Stone, James R.; Mino-Kenudson, Mari; Christensen, James G.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

2013-01-01

Summary Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74–ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the meta-static sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.) PMID:23724914

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

PubMed Central

Kong, Xiangju; Hong, Aayoung; Koya, Richard C.; Moriceau, Gatien; Chodon, Thinle; Guo, Rongqing; Johnson, Douglas B.; Dahlman, Kimberly B.; Kelley, Mark C.; Kefford, Richard F.; Chmielowski, Bartosz; Glaspy, John A.; Sosman, Jeffrey A.; van Baren, Nicolas; Long, Georgina V.; Ribas, Antoni; Lo, Roger S.

2013-01-01

BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses. PMID:24265155

Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab1

PubMed Central

Iida, Mari; Brand, Toni M; Starr, Megan M; Li, Chunrong; Huppert, Evan J; Luthar, Neha; Pedersen, Mikkel W; Horak, Ivan D; Kragh, Michael; Wheeler, Deric L

2013-01-01

The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors. PMID:24204198

Antimicrobial resistance among Escherichia coli that cause childhood community-acquired urinary tract infections in Northern Italy

PubMed Central

2011-01-01

Abstracts Background Resistance rate of Escherichia coli against antimicrobials that are commonly prescribed in pediatric urinary tract infections is currently a matter of concern. Methods The antimicrobial susceptibility patterns of uropathogenic Escherichia coli strains to the common antibimcrobials ampicillin, cotrimoxazole, coamoxyclav, ceftazidime, ceftriaxone, nitrofurantoin, and gentamycin were determined in 177 children aged from 2 to 36 months. They presented with their first symptomatic community acquired urinary tract infection at the Department of Pediatrics, San Leopoldo Mandic Hospital, Merate-Lecco. Results High rates of ampicillin (inpatients: 50%; outpatients: 52%) resistance were identified. The resistance for cotrimoxazole (inpatients: 22%; outpatients: 15%) and especially coamoxyclav (inpatients: 6%; outpatients: 10%) was less pronounced than that to ampicillin. No resistance or less than 1% of resistance was identified for ceftazidime, ceftriaxone, nitrofurantoin, and gentamycin both in inpatients and in outpatients. Conclusions Italian children affected with a community acquired urinary tract infection are initially managed orally with coamoxyclav or parenterally with ceftriaxone. The results of the present retrospective analysis support this attitude. Parenteral ceftriaxone or an aminoglycoside should be considered for patients on antimicrobial prophylaxis or recently prescribed antimicrobials. PMID:21211026

Effectiveness and cost-effectiveness of erlotinib versus gefitinib in first-line treatment of epidermal growth factor receptor-activating mutation-positive non-small-cell lung cancer patients in Hong Kong.

PubMed

Lee, Vivian W Y; Schwander, Bjoern; Lee, Victor H F

2014-06-01

To compare the effectiveness and cost-effectiveness of erlotinib versus gefitinib as first-line treatment of epidermal growth factor receptor-activating mutation-positive non-small-cell lung cancer patients. DESIGN. Indirect treatment comparison and a cost-effectiveness assessment. Hong Kong. Those having epidermal growth factor receptor-activating mutation-positive non-small-cell lung cancer. Erlotinib versus gefitinib use was compared on the basis of four relevant Asian phase-III randomised controlled trials: one for erlotinib (OPTIMAL) and three for gefitinib (IPASS; NEJGSG; WJTOG). The cost-effectiveness assessment model simulates the transition between the health states: progression-free survival, progression, and death over a lifetime horizon. The World Health Organization criterion (incremental cost-effectiveness ratio <3 times of gross domestic product/capita: erlotinib versus gefitinib using only these randomised controlled trials in an indirect treatment comparison resulted in a statistically significant progression-free survival difference in favour of erlotinib (indirect treatment comparison hazard ratio=0.33; 95% confidence interval, 0.19-0.58; P=0.0001). The cost-effectiveness assessment model showed that the cost per progression-free life year gained and per quality-adjusted life year gained was at acceptable values of US$39 431 (approximately HK$306 773) and US$62 419 (approximately HK$485 619) for erlotinib versus gefitinib, respectively. The indirect treatment comparison of OPTIMAL versus IPASS shows that erlotinib is significantly more efficacious than gefitinib. Furthermore, the cost-effectiveness assessment indicates that the incremental cost-effectiveness ratios are well within an acceptable

Multidrug-Resistant CTX-M-(15, 9, 2)- and KPC-2-Producing Enterobacter hormaechei and Enterobacter asburiae Isolates Possessed a Set of Acquired Heavy Metal Tolerance Genes Including a Chromosomal sil Operon (for Acquired Silver Resistance).

PubMed

Andrade, Leonardo N; Siqueira, Thiago E S; Martinez, Roberto; Darini, Ana Lucia C

2018-01-01

Bacterial resistance to antibiotics is concern in healthcare-associated infections. On the other hand, bacterial tolerance to other antimicrobials, like heavy metals, has been neglected and underestimated in hospital pathogens. Silver has long been used as an antimicrobial agent and it seems to be an important indicator of heavy metal tolerance. To explore this perspective, we searched for the presence of acquired silver resistance genes ( sil operon: silE, silS, silR, silC, silF, silB, silA , and silP ) and acquired extended-spectrum cephalosporin and carbapenem resistance genes ( bla CTX-M and bla KPC ) in Enterobacter cloacae Complex (EcC) ( n = 27) and Enterobacter aerogenes ( n = 8) isolated from inpatients at a general hospital. Moreover, the genetic background of the silA (silver-efflux pump) and the presence of other acquired heavy metal tolerance genes, pcoD (copper-efflux pump), arsB (arsenite-efflux pump), terF (tellurite resistance protein), and merA (mercuric reductase) were also investigated. Outstandingly, 21/27 (78%) EcC isolates harbored silA gene located in the chromosome. Complete sil operon was found in 19/21 silA -positive EcC isolates. Interestingly, 8/20 (40%) E. hormaechei and 5/6 (83%) E. asburiae co-harbored silA/pcoD genes and bla CTX-M-(15,2,or9) and/or bla KPC-2 genes. Frequent occurrences of arsB, terF , and merA genes were detected, especially in silA/pcoD -positive, multidrug-resistant (MDR) and/or CTX-M-producing isolates. Our study showed co-presence of antibiotic and heavy metal tolerance genes in MDR EcC isolates. In our viewpoint, there are few studies regarding to bacterial heavy metal tolerance and we call attention for more investigations and discussion about this issue in different hospital pathogens.

Multidrug-Resistant CTX-M-(15, 9, 2)- and KPC-2-Producing Enterobacter hormaechei and Enterobacter asburiae Isolates Possessed a Set of Acquired Heavy Metal Tolerance Genes Including a Chromosomal sil Operon (for Acquired Silver Resistance)

PubMed Central

Andrade, Leonardo N.; Siqueira, Thiago E. S.; Martinez, Roberto; Darini, Ana Lucia C.

2018-01-01

Bacterial resistance to antibiotics is concern in healthcare-associated infections. On the other hand, bacterial tolerance to other antimicrobials, like heavy metals, has been neglected and underestimated in hospital pathogens. Silver has long been used as an antimicrobial agent and it seems to be an important indicator of heavy metal tolerance. To explore this perspective, we searched for the presence of acquired silver resistance genes (sil operon: silE, silS, silR, silC, silF, silB, silA, and silP) and acquired extended-spectrum cephalosporin and carbapenem resistance genes (blaCTX−M and blaKPC) in Enterobacter cloacae Complex (EcC) (n = 27) and Enterobacter aerogenes (n = 8) isolated from inpatients at a general hospital. Moreover, the genetic background of the silA (silver-efflux pump) and the presence of other acquired heavy metal tolerance genes, pcoD (copper-efflux pump), arsB (arsenite-efflux pump), terF (tellurite resistance protein), and merA (mercuric reductase) were also investigated. Outstandingly, 21/27 (78%) EcC isolates harbored silA gene located in the chromosome. Complete sil operon was found in 19/21 silA-positive EcC isolates. Interestingly, 8/20 (40%) E. hormaechei and 5/6 (83%) E. asburiae co-harbored silA/pcoD genes and blaCTX−M−(15,2,or9) and/or blaKPC−2 genes. Frequent occurrences of arsB, terF, and merA genes were detected, especially in silA/pcoD-positive, multidrug-resistant (MDR) and/or CTX-M-producing isolates. Our study showed co-presence of antibiotic and heavy metal tolerance genes in MDR EcC isolates. In our viewpoint, there are few studies regarding to bacterial heavy metal tolerance and we call attention for more investigations and discussion about this issue in different hospital pathogens. PMID:29628916

Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma

PubMed Central

Liu, Jianhua; Liu, Yahui; Meng, Lingyu; Liu, Kai; Ji, Bai

2017-01-01

Molecule-targeted therapy, such as sorafenib, is one of the effectively therapeutic options for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib has been found in some HCC patients, resulting in poor prognosis. It is reported that PD-L1 and DNA methyltransferases (DNMTs) contribute to drug resistance. In this study, by inducing sorafenib-resistant HCC cell lines, we investigated their molecular and functional characteristics. Our data indicated that highly upregulated DNMT1 was positively correlated with PD-L1 overexpression in sorafenib-resistant HCC cells. We demonstrate that PD-L1 regulate DNMT1 through STAT3 signaling pathway. Knockdown of PD-L1 induced DNMT1-dependent DNA hypomethylation and restored the expression of methylation-silenced CDH1. Moreover, inactivation of NFκB blocked PD-L1/STAT3/DNMT1 pathway in sorafenib-resistant HCC cells. Functionally, genetic or pharmacological disruption of PD-L1 or/and DNMT1 sensitize HCC resistance to sorafenib. Importantly, dual inactivation of PD-L1 and DNMT1 by their inhibitor synergistically disrupts the colony formation of sorafenib-resistant HCC cells. These results demonstrate that targeting NFκB/PDL1/STAT3/DNMT1 axis is a new therapeutic strategy for preventing or overcoming the acquired resistance to sorafenib in HCC patients. PMID:28627705

Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model.

PubMed

Omachi, Kohei; Miyakita, Rui; Fukuda, Ryosuke; Kai, Yukari; Suico, Mary Ann; Yokota, Tsubasa; Kamura, Misato; Shuto, Tsuyoshi; Kai, Hirofumi

2017-12-01

Alport syndrome (AS) is a hereditary kidney disease caused by mutation of type IV collagen. Loss of collagen network induces collapse of glomerular basement membrane (GBM) structure. The previous studies showed that upregulation of some tyrosine kinase receptors signaling accompanied GBM disorder in AS mouse model. EGFR signaling is one of the well-known receptor kinase signaling that is involved in glomerular diseases. However, whether EGFR signaling is relevant to AS progression is still uninvestigated. Here, we determined the involvement of EGFR in AS and the effect of suppressing EGFR signaling by erlotinib treatment on AS progression. Phosphorylated EGFR expression was investigated by Western blotting analysis and immunostaining of kidney tissues of Col4a5 mutant mice (a mouse model of X-linked AS). To check the effect of blocking EGFR signaling in AS, we administered erlotinib to AS mice once a day (10 mg/kg/day) orally for 18 weeks. Renal function parameters (proteinuria, serum creatinine, and BUN) and renal histology were assessed, and the gene expressions of inflammatory cytokines were analyzed in renal tissues. Phosphorylated EGFR expression was upregulated in AS mice kidney tissues. Erlotinib slightly reduced the urinary protein and suppressed the expression of renal injury markers (Lcn2, Lysozyme) and inflammatory cytokines (Il-6, Il-1β and KC). Erlotinib did not improve renal pathology, such as glomerular sclerosis and fibrosis. These findings suggest that EGFR signaling is upregulated in kidney, but although inhibiting this signaling pathway suppressed renal inflammatory cytokines, it did not ameliorate renal dysfunction in AS mouse model.

Tumors acquire inhibitor of apoptosis protein (IAP)-mediated apoptosis resistance through altered specificity of cytosolic proteolysis.

PubMed

Hong, Xu; Lei, Lu; Glas, Rickard

2003-06-16

Many tumors overexpress members of the inhibitor of apoptosis protein (IAP) family. IAPs contribute to tumor cell apoptosis resistance by the inhibition of caspases, and are degraded by the proteasome to allow further progression of apoptosis. Here we show that tumor cells can alter the specificity of cytosolic proteolysis in order to acquire apoptosis resistance, which promotes formation of rapidly growing tumors. Survival of tumor cells with low proteasomal activity can occur in the presence of high expression of Tri-peptidyl-peptidase II (TPP II), a large subtilisin-like peptidase that complements proteasomal activity. We find that this state leaves tumor cells unable of effectively degrading IAPs, and that cells in this state form rapidly growing tumors in vivo. We also find, in studies of apoptosis resistant cells derived from large in vivo tumors, that these have acquired an altered peptidase activity, with up-regulation of TPP II activity and decreased proteasomal activity. Importantly, we find that growth of subcutaneous tumors is limited by maintenance of the apoptosis resistant phenotype. The apoptosis resistant phenotype was reversed by increased expression of Smac/DIABLO, an antagonist of IAP molecules. Our data suggest a reversible mechanism in regulation of apoptosis resistance that drives tumor progression in vivo. These data are relevant in relation to the multitude of therapy-resistant clinical tumors that have increased levels of IAP molecules.

Initial Results of a Phase I Dose-Escalation Trial of Concurrent and Maintenance Erlotinib and Reirradiation for Recurrent and New Primary Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rusthoven, Kyle E.; Feigenberg, Steven J.; Raben, David

2010-11-15

Purpose: To present the first report of a Phase I trial evaluating concurrent and maintenance erlotinib and reirradiation in patients with recurrent or secondary primary head-and-neck cancer (HNC). Methods and Materials: Patients with recurrent or new primary HNC with an interval of at least 6 months since prior radiation were eligible. Patients were treated in 3 sequential cohorts: Cohort I, 100 mg of erlotinib daily with reirradiation at 61.6 Gy in 28 fractions; Cohort II, 150 mg of erlotinib with 61.6 Gy in 28 fractions; and Cohort III, 150 mg of erlotinib with 66 Gy in 30 fractions. Maintenance erlotinibmore » started immediately after reirradiation at 150 mg daily and was continued for 2 years or until disease progression or dose-limiting toxicity. Dose-limiting toxicities were defined as any Grade 4 or 5 toxicity or a toxicity-related delay in radiation therapy of greater than 7 days. Results: Fourteen patients were accrued, 3 to Cohort I, 4 to Cohort II, and 7 to Cohort III. Thirteen patients were evaluable for toxicity. Median follow-up was 8.4 months overall and 15.1 months for surviving patients. One patient had a dose-limiting toxicity in Cohort III. This patient declined initial percutaneous endoscopic gastrostomy tube placement, was hospitalized with Grade 3 dysphagia and aspiration, and required a delay in radiation therapy of greater than 7 days. No Grade 4 acute toxicity was observed. Acute Grade 3 toxicity occurred in 9 of 13 patients. No erlotinib-related toxicity of Grade 3 or greater was observed during maintenance therapy. One patient had Grade 5 carotid hemorrhage 6 months after reirradiation, and another patient had Grade 3 osteoradionecrosis. Conclusions: Reirradiation (66 Gy in 2.2 Gy fractions) with concurrent and maintenance erlotinib (150 mg daily) for recurrent or new primary HNC is feasible.« less

Antimicrobial resistance in Hispanic patients hospitalized in San Antonio, TX with community-acquired pneumonia.

PubMed

Restrepo, Marcos I; Velez, Maria I; Serna, Gloria; Anzueto, Antonio; Mortensen, Eric M

2010-11-01

Limited information is available on the antimicrobial resistance of patients with community-acquired pneumonia (CAP) depending on their ethnicity. Our aim was to compare the clinical characteristics, etiology, and microbiological resistance of Hispanic versus non-Hispanic white patients. A retrospective cohort of 601 patients with a diagnosis of CAP included 288 non-Hispanic whites and 313 Hispanics. Penicillin-resistant Streptococcus pneumoniae was more common among Hispanic patients (21.7% vs 0%; P=0.03) but there were no significant differences in macrolide-resistant S pneumoniae, drug-resistant S pneumoniae, or potential or actual multidrug-resistant pathogens (eg, drug-resistant S pneumoniae, methicillin-resistant Staphylococcus aureus, Pseudomonas spp., and Acinetobacter spp.). There were no differences among groups in length of hospital stay, intensive care unit (ICU) admission, or 30-day mortality. This study suggests that Hispanic patients with CAP have a higher rate of penicillin-resistant S pneumoniae, but no differences in antimicrobial resistance, 30-day mortality, ICU admission, or length of stay when compared with non-Hispanic white patients.

[Biochemical and genetic mechanisms for bacteria to acquire aminoglycoside antibiotic resistance].

PubMed

Hotta, K

1997-05-01

Aminoglycoside (AG)-modifying enzymes are the major biochemical basis for the AG resistance of clinically-occurring bacteria. Recent AG resistance profiles can be characterized by the involvement of AAC(6') in combination with other modifying enzymes in Gram negative bacteria. AAC(6')/APH(2") in Staphylococcus aureus is also remarkable. Genetic basis for the emergence or alteration of AG resistance profiles includes point mutations in the regulatory region or specific sites of the coding region of AG-modifying enzyme genes, and rearrangement of the genes caused by transposon and/or integron. In addition, semisynthetic AG antibiotics such as amikacin, arbekacin (ABK) and isepamicin were also reviewed for their stability to AG-modifying enzymes. ABK that has been widely used as an anti-MRSA drug in Japan is distinct from the other AGs because its monoacetylated derivatives (3"-N-acetylABK and 2'-N-acetylABK) by AG acetyltransferases, AAC(3) and AAC(2'), respectively, retain clear antibiotic activities. Based on this novel aspect and the lack of modification sites for APH(3') and ANT(4'), ABK should be regarded as the most refractory AG for bacteria to acquire resistance.

Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study.

PubMed

Wu, Yi-Long; Kim, Joo-Hang; Park, Keunchil; Zaatar, Adel; Klingelschmitt, Gaëlle; Ng, Christina

2012-08-01

Maintenance therapy, commenced immediately after the completion of first-line chemotherapy, is a promising strategy for improving treatment outcomes in patients with non-small-cell lung cancer (NSCLC). The global phase III SequentiAl Tarceva in UnResectable NSCLC (SATURN) study evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib as maintenance treatment in NSCLC patients without progression after first-line chemotherapy. We report a retrospective subanalysis of Asian patients enrolled in SATURN. Patients with advanced NSCLC with no evidence of progression after four cycles of chemotherapy were randomized to receive erlotinib 150 mg/day or placebo, until progressive disease or limiting toxicity. The co-primary endpoints of SATURN were progression-free survival (PFS) in all patients and in those with positive EGFR immunohistochemistry (IHC) status. Secondary endpoints included overall survival (OS), disease control rate, safety, quality of life (QoL) and biomarker analyses. In total, 126 patients from East and South-East Asian centers were randomized (14% of the intent-to-treat population): 88 from Korea, 28 from China and 10 from Malaysia; one patient was excluded from this analysis due to Indian ethnicity. PFS was significantly prolonged in the erlotinib treatment arm, both overall (hazard ratio [HR]: 0.57; p=0.0067) and in patients with EGFR IHC-positive disease (HR=0.50; p=0.0057). There was a trend towards an increase in OS, which reached statistical significance in the EGFR IHC-positive subgroup (p=0.0233). The overall response rate was significantly higher with erlotinib compared with placebo (24% versus 5%; p=0.0025). Erlotinib was generally well tolerated and had no negative impact on QoL in this subpopulation. The most common treatment-related adverse events were rash, diarrhea and pruritus. Erlotinib was effective and well tolerated in Asian patients, producing benefits consistent with those

Community-acquired methicillin-resistant Staphylococcus aureus: an emerging cause of acute bacterial parotitis.

PubMed

Nicolasora, Nelson P; Zacharek, Mark A; Malani, Anurag N

2009-02-01

Staphylococcus aureus has long been recognized as a cause of acute bacterial parotitis. A case of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) parotitis is presented, highlighting the emergence of this increasingly important pathogen to cause a wide variety of infections. Also reviewed are the salient clinical and microbiologic features of this novel infection.

Monoterpenes Support Systemic Acquired Resistance within and between Plants

PubMed Central

Ghirardo, Andrea; Knappe, Claudia; Koch, Kerstin; Dey, Sanjukta; Parker, Jane E.

2017-01-01

This study investigates the role of volatile organic compounds in systemic acquired resistance (SAR), a salicylic acid (SA)-associated, broad-spectrum immune response in systemic, healthy tissues of locally infected plants. Gas chromatography coupled to mass spectrometry analyses of SAR-related emissions of wild-type and non-SAR-signal-producing mutant plants associated SAR with monoterpene emissions. Headspace exposure of Arabidopsis thaliana to a mixture of the bicyclic monoterpenes α-pinene and β-pinene induced defense, accumulation of reactive oxygen species, and expression of SA- and SAR-related genes, including the SAR regulatory AZELAIC ACID INDUCED1 (AZI1) gene and three of its paralogs. Pinene-induced resistance was dependent on SA biosynthesis and signaling and on AZI1. Arabidopsis geranylgeranyl reductase1 mutants with reduced monoterpene biosynthesis were SAR-defective but mounted normal local resistance and methyl salicylate-induced defense responses, suggesting that monoterpenes act in parallel with SA. The volatile emissions from SAR signal-emitting plants induced defense in neighboring plants, and this was associated with the presence of α-pinene, β-pinene, and camphene in the emissions of the “sender” plants. Our data suggest that monoterpenes, particularly pinenes, promote SAR, acting through ROS and AZI1, and likely function as infochemicals in plant-to-plant signaling, thus allowing defense signal propagation between neighboring plants. PMID:28536145

Monoterpenes Support Systemic Acquired Resistance within and between Plants.

PubMed

Riedlmeier, Marlies; Ghirardo, Andrea; Wenig, Marion; Knappe, Claudia; Koch, Kerstin; Georgii, Elisabeth; Dey, Sanjukta; Parker, Jane E; Schnitzler, Jörg-Peter; Vlot, A Corina

2017-06-01

This study investigates the role of volatile organic compounds in systemic acquired resistance (SAR), a salicylic acid (SA)-associated, broad-spectrum immune response in systemic, healthy tissues of locally infected plants. Gas chromatography coupled to mass spectrometry analyses of SAR-related emissions of wild-type and non-SAR-signal-producing mutant plants associated SAR with monoterpene emissions. Headspace exposure of Arabidopsis thaliana to a mixture of the bicyclic monoterpenes α-pinene and β-pinene induced defense, accumulation of reactive oxygen species, and expression of SA- and SAR-related genes, including the SAR regulatory AZELAIC ACID INDUCED1 ( AZI1 ) gene and three of its paralogs. Pinene-induced resistance was dependent on SA biosynthesis and signaling and on AZI1 Arabidopsis geranylgeranyl reductase1 mutants with reduced monoterpene biosynthesis were SAR-defective but mounted normal local resistance and methyl salicylate-induced defense responses, suggesting that monoterpenes act in parallel with SA The volatile emissions from SAR signal-emitting plants induced defense in neighboring plants, and this was associated with the presence of α-pinene, β-pinene, and camphene in the emissions of the "sender" plants. Our data suggest that monoterpenes, particularly pinenes, promote SAR, acting through ROS and AZI1 , and likely function as infochemicals in plant-to-plant signaling, thus allowing defense signal propagation between neighboring plants. © 2017 American Society of Plant Biologists. All rights reserved.

Intratumoral heterogeneity in EGFR mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition

PubMed Central

Soucheray, Margaret; Capelletti, Marzia; Pulido, Inés; Kuang, Yanan; Paweletz, Cloud P.; Becker, Jeffrey H.; Kikuchi, Eiki; Xu, Chunxiao; Patel, Tarun B.; Al-shahrour, Fatima; Carretero, Julián; Wong, Kwok-Kin; Jänne, Pasi A.; Shapiro, Geoffrey I.; Shimamura, Takeshi

2015-01-01

Non-small cell lung cancers (NSCLC) that have developed resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated-EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT, but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared to cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly develops EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele is lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. PMID:26282169

New Real-Time PCR Assays for Detection of Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Group.

PubMed

Shallom, Shamira J; Moura, Natalia S; Olivier, Kenneth N; Sampaio, Elizabeth P; Holland, Steven M; Zelazny, Adrian M

2015-11-01

Members of the Mycobacterium abscessus group (MAG) cause lung, soft tissue, and disseminated infections. The oral macrolides clarithromycin and azithromycin are commonly used for treatment. MAG can display clarithromycin resistance through the inducible erm(41) gene or via acquired mutations in the rrl (23S rRNA) gene. Strains harboring a truncation or a T28C substitution in erm(41) lose the inducible resistance trait. Phenotypic detection of clarithromycin resistance requires extended incubation (14 days), highlighting the need for faster methods to detect resistance. Two real-time PCR-based assays were developed to assess inducible and acquired clarithromycin resistance and tested on a total of 90 clinical and reference strains. A SYBR green assay was designed to distinguish between a full-length and truncated erm(41) gene by temperature shift in melting curve analysis. Single nucleotide polymorphism (SNP) allele discrimination assays were developed to distinguish T or C at position 28 of erm(41) and 23S rRNA rrl gene mutations at position 2058 and/or 2059. Truncated and full-size erm(41) genes were detected in 21/90 and 69/90 strains, respectively, with 64/69 displaying T at nucleotide position 28 and 5/69 containing C at that position. Fifteen isolates showed rrl mutations conferring clarithromycin resistance, including A2058G (11 isolates), A2058C (3 isolates), and A2059G (1 isolate). Targeted sequencing and phenotypic assessment of resistance concurred with molecular assay results. Interestingly, we also noted cooccurring strains harboring an active erm(41), inactive erm(41), and/or acquired mutational resistance, as well as slowly growing MAG strains and also strains displaying an inducible resistance phenotype within 5 days, long before the recommended 14-day extended incubation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Trend and seasonality of community-acquired Escherichia coli antimicrobial resistance and its dynamic relationship with antimicrobial use assessed by ARIMA models.

PubMed

Asencio Egea, María Ángeles; Huertas Vaquero, María; Carranza González, Rafael; Herráez Carrera, Óscar; Redondo González, Olga; Arias Arias, Ángel

2017-12-04

We studied the trend and seasonality of community-acquired Escherichia coli resistance and quantified its correlation with the previous use of certain antibiotics. A time series study of resistant community-acquired E. coli isolates and their association with antibiotic use was conducted in a Primary Health Care Area from 2008 to 2012. A Poisson regression model was constructed to estimate the trend and seasonality of E. coli resistance. A significant increasing trend in mean E. coli resistance to cephalosporins, aminoglycosides and nitrofurantoin was observed. Seasonal resistance to ciprofloxacin and amoxicillin-clavulanic acid was significantly higher in autumn-winter. There was a delay of 7, 10 and 12 months between the use of cotrimoxazole (P<0.038), fosfomycin (P<0.024) and amoxicillin-clavulanic acid (P<0.015), respectively, and the occurrence of E. coli resistance. An average delay of 10 months between the previous use of amoxicillin-clavulanic acid, cotrimoxazole and fosfomycin and the appearance of resistant community-acquired E. coli strains was detected. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Identification of genes differentially expressed in association with acquired cisplatin resistance

PubMed Central

Johnsson, A; Zeelenberg, I; Min, Y; Hilinski, J; Berry, C; Howell, S B; Los, G

2000-01-01

The goal of this study was to identify genes whose mRNA levels are differentially expressed in human cells with acquired cisplatin (cDDP) resistance. Using the parental UMSCC10b head and neck carcinoma cell line and the 5.9-fold cDDP-resistant subline, UMSCC10b/Pt-S15, two suppressive subtraction hybridization (SSH) cDNA libraries were prepared. One library represented mRNAs whose levels were increased in the cDDP resistant variant (the UP library), the other one represented mRNAs whose levels were decreased in the resistant cells (the DOWN library). Arrays constructed with inserts recovered from these libraries were hybridized with SSH products to identify truly differentially expressed elements. A total of 51 cDNA fragments present in the UP library and 16 in the DOWN library met the criteria established for differential expression. The sequences of 87% of these cDNA fragments were identified in Genbank. Among the mRNAs in the UP library that were frequently isolated and that showed high levels of differential expression were cytochrome oxidase I, ribosomal protein 28S, elongation factor 1α, α-enolase, stathmin, and HSP70. The approach taken in this study permitted identification of many genes never before linked to the cDDP-resistant phenotype. © 2000 Cancer Research Campaign PMID:10993653

[Community-acquired methicillin-resistant Staphylococcus aureus infections in children].

PubMed

Frick, Marie Antoinette; Moraga-Llop, Fernando A; Bartolomé, Rosa; Larrosa, Nieves; Campins, Magda; Roman, Yuani; Vindel, Ana; Figueras, Concepció

2010-12-01

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections were first reported in the 1990s. Young, healthy individuals are frequently affected. The incidence of CA-MRSA in Spain is increasing. All children seen between August 2006 and January 2009 with CA-MRSA infections were included. The S. aureus isolates were studied by conventional techniques, their antibiotic susceptibility by agar disk diffusion, the presence of mecA gene was detected by multiplex polymerase chain reaction (PCR) and the gene encoding the Panton-Valentine leukocidin (PVL) by conventional PCR. CA-MRSA colonization was studied both in patients and their family members. CA-MRSA was isolated in 15 samples from 12 patients, aged between 6 days and 14 years. Half of them were not native. Eight patients required hospital admission. The most common clinical presentation was skin and soft tissue infection (92%). Secondary CA-MRSA bacteraemia was present in two patients. All strains were PVL producers and two were resistant to macrolides associated to methicillin resistance and one of them was also resistant to lincosamides. An intra-familial transmission was identified. The clinical outcome was favourable in all patients. CA-MRSA infections are emerging in Spain. Empirical treatment of skin and soft tissue infections should not be changed, since their incidence is still low. The drainage of CA-MRSA suppurative infections plays an important role in their treatment. Clindamycin or trimethoprim-sulfamethoxazole should be used for mild or moderate skin and soft tissue infections. Controlling the spread of these strains presents a challenge in the community today. Copyright © 2009 Elsevier España, S.L. All rights reserved.

Update on HIV-1 acquired and transmitted drug resistance in Africa.

PubMed

Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise

2015-01-01

The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.

Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles

NASA Astrophysics Data System (ADS)

Chen, Lijue; She, Xiaodong; Wang, Tao; He, Li; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

2015-08-01

Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The effect and mechanism of 5-FU loaded EGF grafted HMSNs (EGF-HMSNs-5-FU) in overcoming acquired drug resistance in SW480/ADR cells were studied. The EGF-HMSNs were demonstrated to be specifically internalized in EGFR overexpressed SW480/ADR cells via a receptor-mediated endocytosis and can escape from endo-lysosomes. The EGF-HMSNs-5-FU exhibited much higher cytotoxicity on SW480/ADR cells than HMSNs-5-FU and free 5-FU while the plain HMSNs did not show significant cytotoxicity. The mechanism of EGF-HMSNs-5-FU in overcoming drug resistance in SW480/ADR cells could be attributed to the specific internalization of EGF-HMSNs-5-FU in EGFR overexpressed cells which can lead to high intracellular drug accumulation and cause cell death through S phase arrest.Acquired drug resistance (ADR) can be developed in colorectal cancer cells after 5-fluorouracil (5-FU) treatment and diminish the effectiveness of chemotherapy. In this work, acquired 5-FU resistance in the colorectal cancer cell line SW480 was obtained with the up-regulation of dihydropyrimidine dehydrogenase (DPYD) gene expression which can convert 5-FU to its inactive metabolite. To overcome ADR in colorectal cancer, hollow mesoporous silica nanoparticles (HMSNs) grafted with epidermal growth factor (EGF) were used as nanocarriers to deliver 5-FU to colorectal cancer cells with acquired drug resistance. The

Induction of MEK/ERK activity by AZD8055 confers acquired resistance in neuroblastoma.

PubMed

Xu, Dong-Qing; Toyoda, Hidemi; Qi, Lei; Morimoto, Mari; Hanaki, Ryo; Iwamoto, Shotaro; Komada, Yoshihiro; Hirayama, Masahiro

2018-05-15

Mammalian target of rapamycin (mTOR) complex (mTORC) is frequently activated in diverse cancers. Although dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. AZD8055 is a novel, potent ATP-competitive and specific inhibitor of mTOR kinase activity, which blocks both mTORC1 and mTORC2 activation. In this study, we acquired AZD8055-resistant neuroblastoma (NB) cell sublines by using prolonged stepwise escalation of AZD8055 exposure (4-12 weeks). Here we demonstrate that the AZD8055-resistant sublines (TGW-R and SMS-KAN-R) exhibited marked resistance to AZD8055 compared to the parent cells (TGW and SMS-KAN). The cell cycle G1/S transition was advanced in resistant cells. In addition, the resistance against AZD8055 correlated with over-activation of MEK/ERK signaling pathway. Furthermore, combination of AZD8055 and MEK inhibitor U0126 enhanced the growth inhibition of resistant cells significantly in vitro and in vivo. In conclusion, these data show that targeting mTOR kinase and MEK/ERK signaling simultaneously might help to overcome AZD8055 resistance in NB. Copyright © 2018 Elsevier Inc. All rights reserved.

STAT3-targeted treatment with silibinin overcomes the acquired resistance to crizotinib in ALK-rearranged lung cancer.

PubMed

Cuyàs, Elisabet; Pérez-Sánchez, Almudena; Micol, Vicente; Menendez, Javier A; Bosch-Barrera, Joaquim

2016-12-16

The signal transducer and activator of transcription 3 (STAT3) has been suggested to play a prominent role in mediating non-small-cell lung cancer (NSCLC) resistance to some tyrosine kinase inhibitor (TKI)-mediated therapies. Using a model of anaplastic lymphoma kinase gene (ALK)-translocated NSCLC with acquired resistance to the ALK TKI crizotinib, but lacking amplifications or mutations in the kinase domain of ALK, we herein present evidence that STAT3 activation is a novel mechanism of crizotinib resistance that involves the upregulation of immune escape and epithelial to mesenchymal transition (EMT) signaling pathways. Taking advantage of the flavonolignan silibinin as a naturally occurring STAT3-targeted pharmacological inhibitor, we confirmed that STAT3 activation protects ALK-translocated NSCLC from crizotinib. Accordingly, silibinin-induced inhibition of STAT3 worked synergistically with crizotinib to reverse acquired resistance and restore sensitivity in crizotinib-resistant cells. Moreover, silibinin treatment significantly inhibited the upregulation of the immune checkpoint regulator PD-L1 and also EMT regulators (e.g., SLUG, VIM, CD44) in crizotinib-refractory cells. These findings provide a valuable strategy to potentially improve the efficacy of ALK inhibition by cotreatment with silibinin-based therapeutics, which merit clinical investigation for ALK TKI-resistant NSCLC patients.

Network Meta-Analysis of Erlotinib, Gefitinib, Afatinib and Icotinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations

PubMed Central

Zhao, Yuanyuan; Yang, Yunpeng; Hu, Zhihuang; Xue, Cong; Zhang, Jing; Zhang, Jianwei; Ma, Yuxiang; Zhou, Ting; Yan, Yue; Hou, Xue; Qin, Tao; Dinglin, Xiaoxiao; Tian, Ying; Huang, Peiyu; Huang, Yan; Zhao, Hongyun; Zhang, Li

2014-01-01

Background Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons. Methods We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments. Results Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib. Conclusions The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients

Network meta-analysis of erlotinib, gefitinib, afatinib and icotinib in patients with advanced non-small-cell lung cancer harboring EGFR mutations.

PubMed

Liang, Wenhua; Wu, Xuan; Fang, Wenfeng; Zhao, Yuanyuan; Yang, Yunpeng; Hu, Zhihuang; Xue, Cong; Zhang, Jing; Zhang, Jianwei; Ma, Yuxiang; Zhou, Ting; Yan, Yue; Hou, Xue; Qin, Tao; Dinglin, Xiaoxiao; Tian, Ying; Huang, Peiyu; Huang, Yan; Zhao, Hongyun; Zhang, Li

2014-01-01

Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons. We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments. Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib. The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed

Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the 'Arbeitsgemeinschaft Internistische Onkologie'.

PubMed

Boeck, Stefan; Vehling-Kaiser, Ursula; Waldschmidt, Dirk; Kettner, Erika; Märten, Angela; Winkelmann, Cornelia; Klein, Stefan; Kojouharoff, Georgi; Gauler, Thomas; Fischer von Weikersthal, Ludwig; Clemens, Michael R; Geissler, Michael; Greten, Tim F; Hegewisch-Becker, Susanna; Neugebauer, Sascha; Heinemann, Volker

2010-01-01

To date, only limited toxicity data are available for the combination of erlotinib with either capecitabine or gemcitabine as front-line therapy for advanced pancreatic cancer. Within a randomized phase III trial, 281 treatment-naive patients were randomly assigned between capecitabine (2000 mg/m/day, for 14 days, once every 3 weeks) plus erlotinib (150 mg/day, arm A) and gemcitabine (1000 mg/m as a 30-min infusion) plus erlotinib (150 mg/day, arm B). In case of treatment failure, patients were crossed over to a second-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was the time to treatment failure of second-line therapy (TTF2). This interim analysis of toxicity contains safety data from the first 127 randomized patients. During first-line therapy, patients received a median number of three treatment cycles (range 0-13) in both the arms. Regarding chemotherapy, a treatment delay was observed in 12% of the cycles in arm A and in 22% of the cycles in arm B. Dose reductions of the cytostatic drug were performed in 18 and 27% of treatment cycles, respectively. Erlotinib dose reductions were performed in 6 and 11% of all cycles. Grade 3/4 hematological toxicity was <10% in both the arms; major grade 3/4 toxicities in arms A and B were diarrhea (9 vs. 7%), skin rash (4 vs. 12%), and hand-foot syndrome (7 vs. 0%). No treatment-related death was observed. In conclusion, this interim safety analysis suggests that treatment with erlotinib 150 mg/day is feasible in combination with capecitabine or gemcitabine.

Pneumococcal antimicrobial resistance: therapeutic strategy and management in community-acquired pneumonia.

PubMed

Aspa, Javier; Rajas, Olga; de Castro, Felipe Rodríguez

2008-02-01

Streptococcus pneumoniae has been consistently shown to represent the most frequent causative agent of community-acquired pneumonia (CAP) and pneumococcal antibiotic resistance towards different families of antibiotics continues to be a much-debated issue. Microbial resistance causes a great deal of confusion in choosing an empirical treatment for pneumonia and this makes it necessary to know which factors actually determine the real impact of antimicrobial resistance on the outcome of pneumococcal infections. Several different aspects have to be taken into account when analyzing this matter, such as the study design, the condition of the patient at the time of diagnosis, the choice of the initial antimicrobial regimen (combination or monotherapy) and the pharmacokinetic/pharmacodynamic variables of the chosen antibiotic. It is generally accepted that in the treatment of beta-lactam-resistant pneumococcal infections, the use of standard antipneumococcal beta-lactam agents is unlikely to impact negatively on the outcome of CAP when appropriate agents are given in sufficient doses. As a general rule, for infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will be effective; in the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment although higher dosages are recommended; finally, infections with isolates of high-level penicillin resistance should be treated with alternative agents such as the third-generation cephalosporins or the new antipneumococcal fluoroquinolones. In areas of high prevalence of high-level macrolide resistance, empirical monotherapy with a macrolide is not optimal for the treatment of hospitalised patients with moderate or moderately-severe CAP. Fluoroquinolones are considered to be excellent antibiotics in the treatment of pneumococcal CAP in adults, but their general recommendation has been withheld due to fears of a widespread development

Prevalence of quinolone resistance mechanisms in Enterobacteriaceae producing acquired AmpC β-lactamases and/or carbapenemases in Spain.

PubMed

Machuca, Jesús; Agüero, Jesús; Miró, Elisenda; Conejo, María Del Carmen; Oteo, Jesús; Bou, Germán; González-López, Juan José; Oliver, Antonio; Navarro, Ferran; Pascual, Álvaro; Martínez-Martínez, Luis

2017-10-01

Quinolone resistance in Enterobacteriaceae species has increased over the past few years, and is significantly associated to beta-lactam resistance. The aim of this study was to evaluate the prevalence of chromosomal- and plasmid-mediated quinolone resistance in acquired AmpC β-lactamase and/or carbapenemase-producing Enterobacteriaceae isolates. The presence of chromosomal- and plasmid-mediated quinolone resistance mechanisms [mutations in the quinolone resistance determining region (QRDR) of gyrA and parC and qnr, aac(6')-Ib-cr and qepA genes] was evaluated in 289 isolates of acquired AmpC β-lactamase- and/or carbapenemase-producing Enterobacteriaceae collected between February and July 2009 in 35 Spanish hospitals. Plasmid mediated quinolone resistance (PMQR) genes were detected in 92 isolates (31.8%), qnr genes were detected in 83 isolates (28.7%), and the aac(6')-Ib-cr gene was detected in 20 isolates (7%). qnrB4 gene was the most prevalent qnr gene detected (20%), associated, in most cases, with DHA-1. Only 14.6% of isolates showed no mutations in gyrA or parC with a ciprofloxacin MIC of 0.5mg/L or higher, whereas PMQR genes were detected in 90% of such isolates. qnrB4 gene was the most prevalent PMQR gene detected, and was significantly associated with acquired AmpC β-lactamase DHA-1. PMQR determinants in association with other chromosomal-mediated quinolone resistance mechanisms, different to mutations in gyrA and parC (increased energy-dependent efflux, altered lipopolysaccharide or porin loss), could lead to ciprofloxacin MIC values that exceed breakpoints established by the main international committees to define clinical antimicrobial susceptibility breakpoints. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: a retrospective study.

PubMed

Shinohara, Akira; Ikeda, Masafumi; Okuyama, Hiroyuki; Kobayashi, Misaki; Funazaki, Hideki; Mitsunaga, Shuichi; Shimizu, Satoshi; Ohno, Izumi; Takahashi, Hideaki; Ichida, Yasuhiko; Takahashi, Kunio; Okusaka, Takuji; Saitoh, Shinichiro

2015-06-01

Erlotinib has been reported as being associated with a high incidence of skin toxicities such as acneiform rash, paronychia, and xerosis. The aim of this study was to evaluate the efficacy of prophylactic minocycline treatment for the skin toxicities induced by erlotinib as compared with deferred minocycline treatment in patients with pancreatic cancer treated with erlotinib plus gemcitabine. A total of 96 patients were studied retrospectively, of whom 44 received prophylactic minocycline between August 2012 and June 2013 and 52 received deferred minocycline treatment between August 2011 and July 2012 at the National Cancer Center Hospital East, Kashiwa, Japan. In the prophylactic minocycline group, 200 mg/day oral minocycline was prophylactically administered during the treatment period. The incidence rate of acneiform rash and xerosis of any grade during the first 6 weeks of treatment was significantly reduced in the prophylactic minocycline group compared with the deferred minocycline treatment group (47.7 vs. 80.8%, p<0.001; 2.3 vs. 19.2%, p=0.01). Multivariate analysis identified prophylactic minocycline as a significant independent factor associated with the incidence of acneiform rash and xerosis of any severity (odds ratio [OR] 0.16, 95% confidence interval [CI] 0.06-0.46, p<0.001; OR 0.11, 95% CI 0.01-0.90, p=0.04). Prophylactic minocycline appears to be useful for the management of erlotinib-related acneiform rash and xerosis during chemotherapy in patients with advanced pancreatic cancer.

Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors

PubMed Central

Katayama, Ryohei; Fang, Siyang; Tsutsui, Saki; Akatsuka, Akinobu; Shan, Mingde; Choi, Hyeong-Wook; Fujita, Naoya; Yoshimatsu, Kentaro; Shiina, Isamu; Yamori, Takao; Dan, Shingo

2018-01-01

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) were demonstrated to provide survival benefit in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR; however, emergence of acquired resistance to EGFR-TKIs has been shown to cause poor outcome. To overcome the TKI resistance, drugs with different mode of action are required. We previously reported that M-COPA (2-methylcoprophilinamide), a Golgi disruptor, suppressed the growth of gastric cancers overexpressing receptor tyrosine kinases (RTKs) such as hepatocyte growth factor receptor (MET) via downregulating their cell surface expression. In this study, we examined the antitumor effect of M-COPA on NSCLC cells with TKI resistance. As a result, M-COPA effectively downregulated cell surface EGFR and its downstream signals, and finally exerted in vivo antitumor effect in NSCLC cells harboring secondary (T790M/del19) and tertiary (C797S/T790M/del19) mutated EGFR, which exhibit acquired resistance to first- and third generation EGFR-TKIs, respectively. M-COPA also downregulated MET expression potentially involved in the acquired resistance to EGFR-TKIs via bypassing the EGFR pathway blockade. These results provide the first evidence that targeting the Golgi apparatus might be a promising therapeutic strategy to overcome the vicious cycle of TKI resistance in EGFR-mutated NSCLC cells via downregulating cell surface RTK expression. PMID:29416720

Turning EGFR mutation-positive non-small-cell lung cancer into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors

PubMed Central

Hirsh, Vera

2018-01-01

Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available for the management of EGFR mutation-positive non-small-cell lung cancer (NSCLC), with others in development. Although tumors are exquisitely sensitive to these agents, acquired resistance is inevitable. Furthermore, emerging data indicate that first- (erlotinib and gefitinib), second- (afatinib) and third-generation (osimertinib) EGFR TKIs differ in terms of efficacy and tolerability profiles. Therefore, there is a strong imperative to optimize the sequence of TKIs in order to maximize their clinical benefit. Osimertinib has demonstrated striking efficacy as a second-line treatment option in patients with T790M-positive tumors, and also confers efficacy and tolerability advantages over first-generation TKIs in the first-line setting. However, while accrual of T790M is the most predominant mechanism of resistance to erlotinib, gefitinib and afatinib, resistance mechanisms to osimertinib have not been clearly elucidated, meaning that possible therapy options after osimertinib failure are not clear. At present, few data comparing sequential regimens in patients with EGFR mutation-positive NSCLC are available and prospective clinical trials are required. This article reviews the similarities and differences between EGFR TKIs, and discusses key considerations when assessing optimal sequential therapy with these agents for the treatment of EGFR mutation-positive NSCLC. PMID:29383041

Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments.

PubMed

Wang, Debby D; Ma, Lichun; Wong, Maria P; Lee, Victor H F; Yan, Hong

2015-01-01

EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For 168 clinical subjects, we characterized their corresponding EGFR mutations using molecular interactions, with three potential dimerization partners (ErbB-2, IGF-1R and c-Met) of EGFR and two of its small molecule inhibitors (gefitinib and erlotinib). Based on molecular dynamics simulations and structural analysis, we modeled these mutant-partner or mutant-inhibitor interactions using binding free energy and its components. As a consequence, the mutant-partner interactions are amplified for mutants L858R and L858R_T790M, compared to the wild type EGFR. Mutant delL747_P753insS represents the largest difference between the mutant-IGF-1R interaction and the mutant-inhibitor interaction, which explains the shorter progression-free survival of an inhibitor to this mutant type. Besides, feature sets including different energy components were constructed, and efficient regression trees were applied to map these features to the progression-free survival of an inhibitor. On the other hand, we comparably examined the interactions between ErbB-3 and its partners (EGFR mutants, IGF-1R, ErbB-2 and c-Met). Compared to others, c-Met shows a remarkably-strong binding with ErbB-3, implying its significant role in regulating ErbB-3 signaling. Moreover, EGFR mutants corresponding to poor clinical outcomes, such as L858R_T790M, possess lower binding affinities with ErbB-3 than c-Met does. This may promote the communication between ErbB-3 and c-Met in these cancer cells. The analysis verified

The phosphatase inhibitor menadione (vitamin K3) protects cells from EGFR inhibition by erlotinib and cetuximab.

PubMed

Perez-Soler, Roman; Zou, Yiyu; Li, Tianhong; Ling, Yi He

2011-11-01

Skin toxicity is the main side effect of epidermal growth factor receptor (EGFR) inhibitors, often leading to dose reduction or discontinuation. We hypothesized that phosphatase inhibition in the skin keratinocytes may prevent receptor dephosphorylation caused by EGFR inhibitors and be used as a new potential strategy for the prevention or treatment of this side effect. Menadione (Vitamin K3) was used as the prototype compound to test our hypothesis. HaCat human skin keratinocyte cells and A431 human squamous carcinoma cells were used. EGFR inhibition was measured by Western blotting and immunofluorescence. Phosphatase inhibition and reactive oxygen species (ROS) generation were measured by standard ELISA and fluorescence assays. Menadione caused significant and reversible EGFR activation in a dose-dependent manner starting at nontoxic concentrations. EGFR activation by menadione was associated with reversible protein tyrosine phosphatase inhibition, which seemed to be mediated by ROS generation as exposure to antioxidants prevented both menadione-induced ROS generation and phosphatase inhibition. Short-term coincubation of cells with nontoxic concentrations of menadione and the EGFR inhibitors erlotinib or cetuximab prevented EGFR dephosphorylation. Seventy-two-hour coincubation of cells with the highest nontoxic concentration of menadione and erlotinib provided for a fourfold cell growth inhibitory protection in HaCat human keratinocyte cells. Menadione at nontoxic concentrations causes EGFR activation and prevents EGFR dephosphorylation by erlotinib and cetuximab. This effect seems to be mediated by ROS generation and secondary phosphatase inhibition. Mild oxidative stress in skin keratinocytes by topical menadione may protect the skin from the toxicity secondary to EGFR inhibitors without causing cytotoxicity. ©2011 AACR

Studies on acquired resistance to Schistosoma mansoni in mice exposed to X-irradiated cercariae

PubMed Central

Perlowagora-Szumlewicz, Alina

1964-01-01

In the first part of this paper current information on acquired resistance to schistosomes is reviewed and related to factors which have led to divergent interpretations of experimental results. The author then reports on and discusses experiments performed by her on the development of challenge infections in mice exposed to X-irradiated cercariae of Schistosoma mansoni. While there is some evidence that resistance to S. mansoni may be developed by such exposure, the author considers present findings equivocal and stresses that further research is needed to clarify the situation. ImagesFIG. 2FIG. 3FIG. 4 PMID:14165059

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

PubMed Central

Guarino, Michael J.; Schneider, Charles J.; Hosford, Martha A.; Brahmer, Julie R.; Rudin, Charles M.; Finckenstein, Friedrich Graf; Philip-Norton, Robyn E.; Lu, Haolan; Weber, Martin R.; Ettinger, David S.

2017-01-01

Purpose To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). Conclusion Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib. PMID:19182243

EGFR-TKI-induced HSP70 degradation and BER suppression facilitate the occurrence of the EGFR T790 M resistant mutation in lung cancer cells.

PubMed

Cao, Xiang; Zhou, Yi; Sun, Hongfang; Xu, Miao; Bi, Xiaowen; Zhao, Zhihui; Shen, Binghui; Wan, Fengyi; Hong, Zhuan; Lan, Lei; Luo, Lan; Guo, Zhigang; Yin, Zhimin

2018-06-28

Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790 M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790 M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation. We show that EGFR-TKI treatment causes increased DNA damage and enhanced gene mutation rates, which are secondary to the EGFR-TKI-induced reduction of HSP70 protein. Importantly, HSP70 overexpression delays the occurrence of Erlotinib-induced EGFR T790 M mutation. We further demonstrate that HSP70 interacts with multiple enzymes in the base excision repair (BER) pathway and promotes not only the efficiency but also the fidelity of BER. Collectively, our findings show that EGFR-TKI treatment facilitates gene mutation and the emergence of EGFR T790 M secondary mutation by the attenuation of BER via induction of HSP70 protein degradation. Copyright © 2018. Published by Elsevier B.V.

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

PubMed

Cohen, Ezra E W; Davis, Darren W; Karrison, Theodore G; Seiwert, Tanguy Y; Wong, Stuart J; Nattam, Sreenivasa; Kozloff, Mark F; Clark, Joseph I; Yan, Duen-Hwa; Liu, Wen; Pierce, Carolyn; Dancey, Janet E; Stenson, Kerstin; Blair, Elizabeth; Dekker, Allison; Vokes, Everett E

2009-03-01

Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall

Acquired resistance to chlorhexidine - is it time to establish an 'antiseptic stewardship' initiative?

PubMed

Kampf, G

2016-11-01

Chlorhexidine digluconate (CHG) is an antimicrobial agent used for different types of applications in hand hygiene, skin antisepsis, oral care, and patient washing. Increasing use raises concern regarding development of acquired bacterial resistance. Published data from clinical isolates with CHG minimum inhibitory concentrations (MICs) were reviewed and compared to epidemiological cut-off values to determine resistance. CHG resistance is rarely found in Escherichia coli, Salmonella spp., Staphylococcus aureus or coagulase-negative staphylococci. In Enterobacter spp., Pseudomonas spp., Proteus spp., Providencia spp. and Enterococcus spp., however, isolates are more often CHG resistant. CHG resistance may be detected in multi-resistant isolates such as extremely drug-resistant Klebsiella pneumoniae. Isolates with a higher MIC are often less susceptible to CHG for disinfection. Although cross-resistance to antibiotics remains controversial, some studies indicate that the overall exposure to CHG increases the risk for resistance to some antibiotic agents. Resistance to CHG has resulted in numerous outbreaks and healthcare-associated infections. On an average intensive care unit, most of the CHG exposure would be explained by hand hygiene agents when liquid soaps or alcohol-based hand rubs contain CHG. Exposure to sub-lethal CHG concentration may enhance resistance in Acinetobacter spp., K. pneumoniae, and Pseudomonas spp., all species well known for emerging antibiotic resistance. In order to reduce additional selection pressure in nosocomial pathogens it seems to make sense to restrict the valuable agent CHG to those indications with a clear patient benefit and to eliminate it from applications without any benefit or with a doubtful benefit. Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Managing Severe Community-Acquired Pneumonia Due to Community Methicillin-Resistant Staphylococcus aureus (MRSA).

PubMed

Kwong, Jason C; Chua, Kyra; Charles, Patrick G P

2012-06-01

Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is a rare, but significant cause of community-acquired pneumonia (CAP). A number of virulence determinants have been implicated in the development of severe community MRSA pneumonia, characterized by multilobar cavitating necrosis in patients without usual risk-factors for pneumonia. Optimal management is uncertain, and is extrapolated from anecdotal experiences with small case series, randomized studies of hospital-acquired pneumonia, and laboratory investigations using in vitro experiments and animal models of MRSA pneumonia. Adequate clinical suspicion, early diagnosis and administration of appropriate antibiotics are necessary for best patient outcomes, although some patients will still do badly even with early anti-MRSA therapy. Vancomycin or linezolid have been recommended as first-line therapy, possibly in combination with other antibiotics. Newer antibiotics such as ceftaroline are still being evaluated.

Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status.

PubMed

Lee, Youngjoo; Han, Ji-Youn; Moon, Sung Ho; Nam, Byung-Ho; Lim, Kun Young; Lee, Geon Kook; Kim, Heung Tae; Yun, Tak; An, Hye Jin; Lee, Jin Soo

2017-10-01

Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status. Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D). Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities. Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.

The battle against multi-resistant strains: Renaissance of antimicrobial essential oils as a promising force to fight hospital-acquired infections.

PubMed

Warnke, Patrick H; Becker, Stephan T; Podschun, Rainer; Sivananthan, Sureshan; Springer, Ingo N; Russo, Paul A J; Wiltfang, Joerg; Fickenscher, Helmut; Sherry, Eugene

2009-10-01

Hospital-acquired infections and antibiotic-resistant bacteria continue to be major health concerns worldwide. Particularly problematic is methicillin-resistant Staphylococcus aureus (MRSA) and its ability to cause severe soft tissue, bone or implant infections. First used by the Australian Aborigines, Tea tree oil and Eucalyptus oil (and several other essential oils) have each demonstrated promising efficacy against several bacteria and have been used clinically against multi-resistant strains. Several common and hospital-acquired bacterial and yeast isolates (6 Staphylococcus strains including MRSA, 4 Streptococcus strains and 3 Candida strains including Candida krusei) were tested for their susceptibility for Eucalyptus, Tea tree, Thyme white, Lavender, Lemon, Lemongrass, Cinnamon, Grapefruit, Clove Bud, Sandalwood, Peppermint, Kunzea and Sage oil with the agar diffusion test. Olive oil, Paraffin oil, Ethanol (70%), Povidone iodine, Chlorhexidine and hydrogen peroxide (H(2)O(2)) served as controls. Large prevailing effective zones of inhibition were observed for Thyme white, Lemon, Lemongrass and Cinnamon oil. The other oils also showed considerable efficacy. Remarkably, almost all tested oils demonstrated efficacy against hospital-acquired isolates and reference strains, whereas Olive and Paraffin oil from the control group produced no inhibition. As proven in vitro, essential oils represent a cheap and effective antiseptic topical treatment option even for antibiotic-resistant strains as MRSA and antimycotic-resistant Candida species.

A Trial-Based Cost-Effectiveness Analysis of Erlotinib Alone versus Platinum-Based Doublet Chemotherapy as First-Line Therapy for Eastern Asian Nonsquamous Non–Small-Cell Lung Cancer

PubMed Central

Wang, Siying; Peng, Liubao; Li, Jianhe; Zeng, Xiaohui; Ouyang, Lihui; Tan, Chongqing; Lu, Qiong

2013-01-01

Introduction Lung cancer, the most prevalent malignant cancer in the world, remains a serious threat to public health. Recently, a large number of studies have shown that an epidermoid growth factor receptor-tyrosine kinase inhibitor (EGFR TKI), Erlotinib, has significantly better efficacy and is better tolerated in advanced non-small cell lung cancer (NSCLC) patients with a positive EGFR gene mutation. However, access to this drug is severely limited in China due to its high acquisition cost. Therefore, we decided to conduct a study to compare cost-effectiveness between erlotinib monotherapy and carboplatin-gemcitabine (CG) combination therapy in patients with advanced EGFR mutation-positive NSCLC. Methods A Markov model was developed from the perspective of the Chinese health care system to evaluate the cost-effectiveness of the two treatment strategies; this model was based on data from the OPTIMAL trial, which was undertaken at 22 centres in China. The 10-year quality-adjusted life years (QALYs), direct costs, and incremental cost-effectiveness ratio (ICER) were estimated. To allow for uncertainties within the parameters and to estimate the model robustness, one-way sensitivity analysis and probabilistic sensitivity analysis were performed. Results The median progression-free survival (PFS) obtained from Markov model was 13.2 months (13.1 months was reported in the trial) in the erlotinib group while and 4.64 months (4.6 months was reported in the trial) in the CG group. The QALYs were 1.4 years in the erlotinib group and 1.96 years in the CG group, indicating difference of 0.56 years. The ICER was most sensitive to the health utility of DP ranged from $58,584.57 to $336,404.2. At a threshold of $96,884, erlotinib had a 50%probability of being cost-effective. Conclusions Erlotinib monotherapy is more cost-effective compared with platinum-based doublets chemotherapy as a first-line therapy for advanced EGFR mutation- positive NSCLC patients from within the

Real-life effectiveness of erlotinib as second-line treatment of stage IIIB/IV squamous non-small cell lung cancer: Results of the PEPiTA observational study.

PubMed

Monnet, Isabelle; Audigier-Valette, Clarisse; Girard, Nicolas; Vergnenègre, Alain; Molinier, Olivier; Souquet, Pierre Jean; Blanchon, François; Bonnetain, Franck; Taguieva-Pioger, Naila; Lamour, Corinne; Wislez, Marie

2016-08-01

Erlotinib, an inhibitor of tyrosine kinase activity of the epidermal growth factor receptor, is effective in non-small cell lung cancer (NSCLC). Data on erlotinib use in squamous NSCLC are limited. This observational study aimed at evaluating the efficacy and safety of second-line erlotinib in patients with stage IIIB/IV squamous NSCLC in a real-life setting. Patients with predominantly squamous stage IIIB/IV NSCLC, who failed first-line platinum-based therapy, were recruited and followed-up for 12 months. Patients underwent visits each trimester. Data were derived from case report forms, and functional assessment of cancer therapy-lung (FACT-L) questionnaires. A total of 152 patients were enrolled; the majority were males (90%) and mean age was 67.7 years. All patients had squamous (97%) or predominantly squamous (3%) NSCLC, of stage IIIB (21%) or IV (79%). Median progression free survival (PFS) and overall survival were 3 and 5.8 months, respectively. Disease progression was observed in the majority of the patients, mostly due to progression of primary tumour and/or metastatic sites, and led to death in 91/107 of patients. Of the 107 deaths reported, none were due to erlotinib. FACT-L questionnaires were interpretable up to the first visit and were in line with PFS data, showing a relatively good quality of life up to Month 3 (mean total score=78.8). No new or unexpected safety issues were reported. The results of this real-life cohort study like those of previous phase III/IV subgroups study analyses indicate that erlotinib is a valuable option for second-line treatment of stage IIIB/IV squamous NSCLC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Budget impact model of adding erlotinib to a regimen of gemcitabine for the treatment of locally advanced, nonresectable or metastatic pancreatic cancer.

PubMed

Danese, Mark D; Reyes, Carolina; Northridge, Kelly; Lubeck, Deborah; Lin, Chin-Yu; O'Connor, Paula

2008-04-01

The aim of this study was to determine the budget impact of adding erlotinib to a US health plan insurer's formulary as a combination therapy with gemcitabine for the treatment of nonresectable pancreatic cancer. An Excel-based budget impact model was developed to evaluate the costs for National Comprehensive Cancer Network guideline-recommended treatment options for patients with locally advanced, nonresectable or metastatic pancreatic cancer from the perspective of a US managed care plan. The model compared treatment with gemcitabine alone and in combination with erlotinib, including the costs of treatment, adverse events (AEs), and administration. Inputs for the model were derived from the Surveillance, Epidemiology and End Results Cancer Registry, clinical trials, and publicly available sources and were varied in sensitivity analyses to identify influential inputs. The model addressed first-line use in a single indication and assumed that the proportion of patients aged >or=65 years in a managed care organization was the same as in the general population. The model did not account for patient copayments for oral medications, a factor that could lower a plan's overall cost further than estimated herein. For a hypothetical managed care plan with 500,000 members, the model estimated 43 newly diagnosed pancreatic cancer cases each year, of which 56% (n=24) would be treated with gemcitabine as first-line therapy. Assuming that erlotinib were added to the treatment regimen in 40% (n=10) of gemcitabine-treated patients for 15.7 weeks of therapy per patient, the expected 1-year cost in 2006 dollars would be US $466,700 compared with $346,700 had all patients been treated with gemcitabine alone. Administration costs accounted for 10% to 12% of total costs, while AE management costs made up 14% to 16% of total costs. These estimates corresponded to an incremental cost of $120,000, or $0.020 per member per month (PMPM). The results were relatively insensitive to drug

Community acquired methicillin resistant Staphylococcus aureus pneumonia: an update for the emergency and intensive care physician.

PubMed

Karampela, I; Poulakou, G; Dimopoulos, G

2012-08-01

Pneumonia caused by community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) among individuals without healthcare-associated (HA) risk factors was first recognized a decade ago. CA-MRSA has now been established as a pathogen responsible for rapidly progressive, frequently fatal disease manifesting as necrotizing pneumonia, severe sepsis and necrotizing fasciitis. The frequency of occurrence, risk factors, and optimal treatment of CA-MRSA pneumonia remain unclear and vary significantly across countries. CA-MRSA is resistant to β-lactam antimicrobials due to the acquisition of novel methicillin resistance genetic cassettes. Additionally many CA-MRSA strains produce Panton-Valentine leukocidin (PVL), due to which they probably exceed the virulence of hospital-acquired MRSA isolates (HA-MRSA). CA-MRSA pneumonia requires early suspicion -especially in young otherwise healthy individuals with rapidly evolving clinical picture presenting with cavitary consolidation, bilateral infiltrates, pleural effusion and hemoptysis. Prompt hospitalization and aggressive treatment with intravenous antibiotics is warranted to improve outcomes. Therapeutic approach for severe CA-MRSA infections and particularly pneumonia is generally the same as that for invasive HA-MRSA infections. New anti-MRSA agents and possible combinations are of great importance to be evaluated in the future.

Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.

PubMed

Hing, Zachary A; Mantel, Rose; Beckwith, Kyle A; Guinn, Daphne; Williams, Erich; Smith, Lisa L; Williams, Katie; Johnson, Amy J; Lehman, Amy M; Byrd, John C; Woyach, Jennifer A; Lapalombella, Rosa

2015-05-14

Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. © 2015 by The American Society of Hematology.

Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors.

PubMed

Shao, Yi; Zhong, Dian-Sheng

2018-04-01

Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8-16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.

The human microbiota: novel targets for hospital-acquired infections and antibiotic resistance.

PubMed

Pettigrew, Melinda M; Johnson, J Kristie; Harris, Anthony D

2016-05-01

Hospital-acquired infections are increasing in frequency due to multidrug resistant organisms (MDROs), and the spread of MDROs has eroded our ability to treat infections. Health care professionals cannot rely solely on traditional infection control measures and antimicrobial stewardship to prevent MDRO transmission. We review research on the microbiota as a target for infection control interventions. We performed a literature review of key research findings related to the microbiota as a target for infection control interventions. These data are summarized and used to outline challenges, opportunities, and unanswered questions in the field. The healthy microbiota provides protective functions including colonization resistance, which refers to the microbiota's ability to prevent colonization and/or expansion of pathogens. Antibiotic use and other exposures in hospitalized patients are associated with disruptions of the microbiota that may reduce colonization resistance and select for antibiotic resistance. Novel methods to exploit protective mechanisms provided by an intact microbiota may provide the key to preventing the spread of MDROs in the health care setting. Research on the microbiota as a target for infection control has been limited. Epidemiologic studies will facilitate progress toward the goal of manipulating the microbiota for control of MDROs in the health care setting. Copyright © 2016 Elsevier Inc. All rights reserved.

Combination therapy of apatinib with icotinib for primary acquired icotinib resistance in patients with advanced pulmonary adenocarcinoma with EGFR mutation.

PubMed

Xia, Pinghui; Cao, Jinlin; Lv, Xiayi; Wang, Luming; Lv, Wang; Hu, Jian

2018-05-01

Multi-targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third-generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression-free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

The spatiotemporal system dynamics of acquired resistance in an engineered microecology.

PubMed

Datla, Udaya Sree; Mather, William H; Chen, Sheng; Shoultz, Isaac W; Täuber, Uwe C; Jones, Caroline N; Butzin, Nicholas C

2017-11-22

Great strides have been made in the understanding of complex networks; however, our understanding of natural microecologies is limited. Modelling of complex natural ecological systems has allowed for new findings, but these models typically ignore the constant evolution of species. Due to the complexity of natural systems, unanticipated interactions may lead to erroneous conclusions concerning the role of specific molecular components. To address this, we use a synthetic system to understand the spatiotemporal dynamics of growth and to study acquired resistance in vivo. Our system differs from earlier synthetic systems in that it focuses on the evolution of a microecology from a killer-prey relationship to coexistence using two different non-motile Escherichia coli strains. Using empirical data, we developed the first ecological model emphasising the concept of the constant evolution of species, where the survival of the prey species is dependent on location (distance from the killer) or the evolution of resistance. Our simple model, when expanded to complex microecological association studies under varied spatial and nutrient backgrounds may help to understand the complex relationships between multiple species in intricate natural ecological networks. This type of microecological study has become increasingly important, especially with the emergence of antibiotic-resistant pathogens.

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147), a Pan-Class I PI3K Inhibitor, in Combination With Erlotinib in Patients With Solid Tumors

PubMed Central

LoRusso, Patricia; Bahleda, Ratislav; Lager, Joanne; Liu, Li; Jiang, Jason; Martini, Jean-François; Macé, Sandrine; Burris, Howard

2015-01-01

Background. This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. Methods. In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50–600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included. Results. Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity. Conclusion. Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors. PMID:25669662

IKK phosphorylation of NF-κB at serine 536 contributes to acquired cisplatin resistance in head and neck squamous cell cancer

PubMed Central

Li, Zhipeng; Yang, Zejia; Lapidus, Rena G; Liu, Xuefeng; Cullen, Kevin J; Dan, Han C

2015-01-01

Current treatment methods for advanced head and neck squamous cell carcinoma (HNSCC) include surgery, radiation therapy and chemotherapy. For recurrent and metastatic HNSCC, cisplatin is the most common treatment option, but most of patients will eventually develop cisplatin resistance. Therefore, it is imperative to define the mechanisms involved in cisplatin resistance and find novel therapeutic strategies to overcome this deadly disease. In order to determine the role of nuclear factor-kappa B (NF-κB) in contributing to acquired cisplatin resistance in HNSCC, the expression and activity of NF-κB and its upstream kinases, IKKα and IKKβ, were evaluated and compared in three pairs of cisplatin sensitive and resistant HNSCC cell lines, including a pair of patient derived HNSCC cell line. The experiments revealed that NF-κB p65 activity was elevated in cisplatin resistant HNSCC cells compared to that in their parent cells. Importantly, the phosphorylation of NF-κB p65 at serine 536 and the phosphorylation of IKKα and IKKβ at their activation loops were dramatically elevated in the resistant cell lines. Furthermore, knockdown of NF-κB or overexpression of p65-S536 alanine (p65-S536A) mutant sensitizes resistant cells to cisplatin. Additionally, the novel IKKβ inhibitor CmpdA has been shown to consistently block the phosphorylation of NF-κB at serine 536 while also dramatically improving the efficacy of cisplatin in inhibition of cell proliferation and induction of apoptosis in the cisplatin resistant cancer cells. These results indicated that IKK/NF-κB plays a pivotal role in controlling acquired cisplatin resistance and that targeting the IKK/NF-κB signaling pathway may provide a possible therapeutic method to overcome the acquired resistance to cisplatin in HNSCC. PMID:26693062

Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases.

PubMed

Isozaki, Hideko; Ichihara, Eiki; Takigawa, Nagio; Ohashi, Kadoaki; Ochi, Nobuaki; Yasugi, Masayuki; Ninomiya, Takashi; Yamane, Hiromichi; Hotta, Katsuyuki; Sakai, Katsuya; Matsumoto, Kunio; Hosokawa, Shinobu; Bessho, Akihiro; Sendo, Toshiaki; Tanimoto, Mitsune; Kiura, Katsuyuki

2016-03-15

Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. ©2015 American Association for Cancer Research.

Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tyler, Andreas, E-mail: andreas.tyler@medbio.umu.se; Johansson, Anders; Karlsson, Terese

Background: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expressionmore » of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance. Methods: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72 h on expression and cisplatin cytotoxicity was tested. Results: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. Conclusions: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin

Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study.

PubMed

Lubner, Sam J; Mahoney, Michelle R; Kolesar, Jill L; Loconte, Noelle K; Kim, George P; Pitot, Henry C; Philip, Philip A; Picus, Joel; Yong, Wei-Peng; Horvath, Lisa; Van Hazel, Guy; Erlichman, Charles E; Holen, Kyle D

2010-07-20

Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.

PubMed

Ciuleanu, Tudor; Stelmakh, Lilia; Cicenas, Saulius; Miliauskas, Skaidrius; Grigorescu, Alexandru Calin; Hillenbach, Carina; Johannsdottir, Hrefna Kristin; Klughammer, Barbara; Gonzalez, Emilio Esteban

2012-03-01

Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC. TITAN was an international, randomised multicentre, open-label, phase 3 study that was done at 77 sites in 24 countries. Chemotherapy-naive patients with locally advanced, recurrent, or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy, after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN. Enrolled patients were randomly assigned (1:1) by a minimisation method to ensure balanced stratification, to receive erlotinib 150 mg/day or chemotherapy (standard docetaxel or pemetrexed regimens, at the treating investigators' discretion), until unacceptable toxicity, disease progression, or death. Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, smoking history, and region of residence. The primary endpoint was overall survival in the intention-to-treat population. TITAN was halted prematurely because of slow recruitment. This study is registered with ClinicalTrials.gov, number NCT00556322. Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27·9 months (IQR 11·0-36·0) in the erlotinib group and 24·8 months (12·1-41·6) in the chemotherapy group. Median overall survival was 5·3 months (95% CI 4·0-6·0) with erlotinib and 5·5 months (4·4-7·1) with chemotherapy (hazard ratio [HR

A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice.

PubMed

Feng, Jia-Hua; Nakagawa-Goto, Kyoko; Lee, Kuo-Hsiung; Shyur, Lie-Fen

2016-06-01

Acquired resistance to vemurafenib develops through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Recent combination therapies such as a MEK inhibitor combined with vemurafenib show improvement in major clinical end points, but the percentage of patients with adverse toxic events is higher than with vemurafenib monotherapy and most patients ultimately relapse. Therefore, there is an urgent need to develop new antimelanoma drugs and/or adjuvant agents for vemurafenib therapy. In this study, we created a novel semiorganically modified derivative, DETD-35, from deoxyelephantopin (DET), a plant sesquiterpene lactone demonstrated as an anti-inflammatory and anti-mammary tumor agent. Our results show that DETD-35 inhibited proliferation of a panel of melanoma cell lines, including acquired vemurafenib resistance A375 cells (A375-R) established in this study, with superior activities to DET and no cytotoxicity to normal melanocytes. DETD-35 suppressed tumor growth and reduced tumor mass as effectively as vemurafenib in A375 xenograft study. Furthermore, DETD-35 also reduced tumor growth in both acquired (A375-R) and intrinsic (A2058) vemurafenib resistance xenograft models, where vemurafenib showed no antitumor activity. Notably, the combination of DETD-35 and vemurafenib exhibited the most significant effects in both in vitro and in vivo xenograft studies due to synergism of the compound and the drug. Mechanistic studies suggested that DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells. Overall, our results suggest that DETD-35 may be useful as a therapeutic or adjuvant agent against BRAF(V600E) mutant and acquired vemurafenib resistance melanoma. Mol Cancer Ther; 15(6); 1163-76. ©2016 AACR. ©2016 American Association for Cancer Research.

Up-regulation of antioxidant enzymes and coenzyme Q(10) in a human oral cancer cell line with acquired bleomycin resistance.

PubMed

Yen, Hsiu-Chuan; Li, Sin-Hua; Majima, Hideyuki J; Huang, Yu-Hsiang; Chen, Chiu-Ping; Liu, Chia-Chi; Tu, Ya-Chi; Chen, Chih-Wei

2011-06-01

Bleomycin (BLM) is an anti-cancer drug that can induce formation of reactive oxygen species (ROS). To investigate the association between up-regulation of antioxidant enzymes and coenzyme Q(10) (CoQ(10)) in acquired BLM resistance, one BLM-resistant clone, SBLM24 clone, was selected from a human oral cancer cell line, SCC61 clone. The BLM resistance of SBLM24 clone relative to a sub-clone of SCC61b cells was confirmed by analysis of clonogenic ability and cell cycle arrest. CoQ(10) levels and levels of Mn superoxide dismutase, glutathione peroxidase 1, catalase and thioredoxin reductase 1 were augmented in SBLM24 clone although there was also a mild increase in the expression of BLM hydrolase. Suppression of CoQ(10) levels by 4-aminobenzoate sensitized BLM-induced cytotoxicity. The results of suppression on enhanced ROS production by BLM and the cross-resistance to hydrogen peroxide in SBLM24 clone further demonstrated the development of adaptation to oxidative stress during the formation of acquired BLM resistance.

Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.

PubMed

Shi, Puyu; Oh, You-Take; Zhang, Guojing; Yao, Weilong; Yue, Ping; Li, Yikun; Kanteti, Rajani; Riehm, Jacob; Salgia, Ravi; Owonikoko, Taofeek K; Ramalingam, Suresh S; Chen, Mingwei; Sun, Shi-Yong

2016-10-01

The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. The current study has demonstrated that Met amplification and hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed amplified Met gene and hyperactivated Met, and were cross-resistant to AZD9291 or erlotinib. Met inhibition overcame the resistance of these cell lines to AZD9291 both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. Hence, we suggest that Met inhibition is also an effective strategy to overcome resistance of certain EGFR-mutated NSCLCs with Met amplification to AZD9291, warranting the further clinical validation of our findings. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

PubMed Central

Peng, Xing-Xiang; Tiwari, Amit K.; Wu, Hsiang-Chun; Chen, Zhe-Sheng

2012-01-01

Imatinib, a breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myelogenous leukemia (CML). However, development of multidrug resistance (MDR) limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line (K562-imatinib) through a stepwise selection process. While characterizing the phenotype of these cells, we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells. In addition, these cells were cross-resistant to second- and third-generation BCR-ABL TKIs. Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein (P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells. In addition, accumulation of [14C]6-mercaptopurine (6-MP) was decreased, whereas the ATP-dependent efflux of [14C] 6-MP and [3H]methotrexate transport were increased in K562-imatinib cells. These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells. PMID:22098951

Effect of United States buckwheat honey on antibiotic-resistant hospital acquired pathogens

PubMed Central

Hammond, Eric Nee-Armah; Duster, Megan; Musuuza, Jackson Ssentalo; Safdar, Nasia

2016-01-01

Introduction Due to an upsurge in antibiotic-resistant infections and lack of therapeutic options, new approaches are needed for treatment. Honey may be one such potential therapeutic option. We investigated the susceptibility of hospital acquired pathogens to four honeys from Wisconsin, United States, and then determined if the antibacterial effect of each honey against these pathogens is primarily due to the high sugar content. Methods Thirteen pathogens including: four Clostridium difficile, two Methicillin-resistant Staphylococcus aureus, two Pseudomonas aeruginosa, one Methicillin-Susceptible Staphylococcus aureus, two Vancomycin-resistance Enterococcus, one Enterococcus faecalis and one Klebsiella pneumoniae were exposed to 1-50% (w/v) four Wisconsin honeys and Artificial honey to determine their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) using the broth dilution method. Results Buckwheat honey predominantly exhibited a bactericidal mode of action against the tested pathogens, and this varied with each pathogen. C. difficile isolates were more sensitive to the Wisconsin buckwheat honey as compared to the other pathogens. Artificial honey at 50% (w/v) failed to kill any of the pathogens. The high sugar content of Wisconsin buckwheat honey is not the only factor responsible for its bactericidal activity. Conclusion Wisconsin buckwheat honey has the potential to be an important addition to therapeutic armamentarium against resistant pathogens and should be investigated further. PMID:28292167

Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma.

PubMed

Kaseb, Ahmed O; Morris, Jeffrey S; Iwasaki, Michiko; Al-Shamsi, Humaid O; Raghav, Kanwal Pratap Singh; Girard, Lauren; Cheung, Sheree; Nguyen, Van; Elsayes, Khaled M; Xiao, Lianchun; Abdel-Wahab, Reham; Shalaby, Ahmed S; Hassan, Manal; Hassabo, Hesham M; Wolff, Robert A; Yao, James C

2016-01-01

Clinicaltrials.gov #NCT01180959. Early clinical studies of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) have a tolerable toxicity and a promising clinical outcome. We evaluated the efficacy and tolerability of this combination as a second-line therapy for HCC refractory to sorafenib. For this single-arm, Phase II study, we recruited patients with Child-Pugh class A or B liver disease, Eastern Cooperative Oncology Group performance status 0-2, and advanced HCC that was not amenable to surgical or regional therapies and treatment with sorafenib had failed (disease progressed or patient could not tolerate sorafenib). Patients received 10 mg/kg intravenous bevacizumab every 14 days and 150 mg oral erlotinib daily for 28-day cycles until progression. Tumor response was evaluated every two cycles using Response Evaluation Criteria in Solid Tumors. The primary end point was the 16-week progression-free survival rate. Secondary end points included time to progression and overall survival. A total of 44 patients were enrolled and had a median follow-up time of 33.8 months (95% confidence interval [CI]: 23.5 months - not defined). The 16-week progression-free survival rate was 43% (95% CI: 28%-59%), median time to progression was 3.9 months (95% CI: 2.0-8.3 months), and median overall survival duration was 9.9 months (95% CI: 8.3-15.5 months). Grade 3-4 adverse events included fatigue (13%), acne (11%), diarrhea (9%), anemia (7%), and upper gastrointestinal hemorrhage (7%). Bevacizumab plus erlotinib was tolerable and showed a signal of survival benefit in the second-line setting for patients with advanced HCC. Because standard-of-care options are lacking in this setting, further studies to identify predictors of response to this regimen are warranted.

Being Met as marked - patients' experiences of being infected with community-acquired methicillin-resistant Staphylococcus aureus (MRSA).

PubMed

Skyman, Eva; Lindahl, Berit; Bergbom, Ingegerd; Sjöström, Harrieth Thunberg; Åhrén, Christina

2016-12-01

It is known that patients who acquired methicillin-resistant Staphylococcus aureus (MRSA) in hospitals suffer and feel as plague. Moreover, the patient interaction with nurses and physicians is described as frightening. Little is known about patient experiences after having acquired CA-MRSA concerning care and everyday life. To reveal and interpret otherwise healthy patients' lived experiences of receiving care and their everyday life after having acquired community MRSA (CA-MRSA). A phenomenological hermeneutic approach guided by Ricouer was conducted. Interviews with twelve patients were transcribed verbatim into a text. The text was analysed in three phases: naive understanding, structural analysis and comprehensive understanding to reveal a possible being in the world. In this study, this referred to what it means to be infected with CA-MRSA. The findings indicate that patients who acquired MRSA experience a changed body image. They suffer from ignorant and frightened behavior from healthcare workers, social contacts, and also of being bullied by colleagues. Despite this, patients assume great responsibility for protecting others. However, knowledgeable staff alleviate suffering and bring peace of mind to the patients. Preventing patient's feelings of being a pest, an outsider living with fear, requires urgent education and understanding about resistant bacteria and how to meet an infected patient. The results describing patients, affected with MRSA, may contribute and touch the readers to better understanding of patient's changed body image and suffering and how to mitigate these feelings. © 2016 Nordic College of Caring Science.

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer.

PubMed

Vaccaro, Vanja; Bria, Emilio; Sperduti, Isabella; Gelibter, Alain; Moscetti, Luca; Mansueto, Giovanni; Ruggeri, Enzo Maria; Gamucci, Teresa; Cognetti, Francesco; Milella, Michele

2013-07-28

To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

PubMed Central

Vaccaro, Vanja; Bria, Emilio; Sperduti, Isabella; Gelibter, Alain; Moscetti, Luca; Mansueto, Giovanni; Ruggeri, Enzo Maria; Gamucci, Teresa; Cognetti, Francesco; Milella, Michele

2013-01-01

AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2 per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of

Acquired resistance to the 16-membered macrolides tylosin and tilmicosin by Mycoplasma bovis.

PubMed

Lerner, Uri; Amram, Eytan; Ayling, Roger D; Mikula, Inna; Gerchman, Irena; Harrus, Shimon; Teff, Dina; Yogev, David; Lysnyansky, Inna

2014-01-31

The molecular mechanism of acquired resistance to the 16-membered macrolides tylosin (Ty) and tilmicosin (Tm) was investigated in Mycoplasma bovis field isolates. Sequence analysis of domains II and V of the two 23S rRNA alleles and ribosomal proteins L4 and L22 was performed on 54 M. bovis isolates showing different minimal inhibitory concentrations (MIC). The presence of any one of the point mutations G748A, C752T, A2058G, A2059G or A2059C (Escherichia coli numbering) in one or both alleles of the 23S rRNAs was correlated with decreased susceptibility to Ty (8-1024 μg/ml) and to Tm (32 to >256 μg/ml) in 27/27 and 27/31 M. bovis isolates, respectively. Although a single mutation in domain II or V could be sufficient to cause decreased susceptibility to Ty, our data imply that a combination of mutations in two domains is necessary to achieve higher MICs (≥ 128 μg/ml). The influence of a combination of mutations in two domains II and V on enhancement of resistance to Tm was less clear. In addition, the amino acid (aa) substitution L22-Q90H was found in 24/32 representative M. bovis isolates with different MICs, but no correlation with decreased susceptibility to Ty or Tm was identified. Multiple aa substitutions were also identified in the L4 protein, including at positions 185-186 (positions 64 and 65 in E. coli) which are adjacent to the macrolide-binding site. This is the first description of the molecular mechanism of acquired resistance to the 16-membered macrolides in M. bovis. Copyright © 2013 Elsevier B.V. All rights reserved.

Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study

PubMed Central

Lubner, Sam J.; Mahoney, Michelle R.; Kolesar, Jill L.; LoConte, Noelle K.; Kim, George P.; Pitot, Henry C.; Philip, Philip A.; Picus, Joel; Yong, Wei-Peng; Horvath, Lisa; Van Hazel, Guy; Erlichman, Charles E.; Holen, Kyle D.

2010-01-01

Purpose Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer. PMID:20530271

A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors.

PubMed

Gray, Jhanelle E; Haura, Eric; Chiappori, Alberto; Tanvetyanon, Tawee; Williams, Charles C; Pinder-Schenck, Mary; Kish, Julie A; Kreahling, Jenny; Lush, Richard; Neuger, Anthony; Tetteh, Leticia; Akar, Angela; Zhao, Xiuhua; Schell, Michael J; Bepler, Gerold; Altiok, Soner

2014-03-15

Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer. Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed. Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02). We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role. ©2014 AACR.

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

PubMed

Philip, Philip A; Mahoney, Michelle R; Holen, Kyle D; Northfelt, Donald W; Pitot, Henry C; Picus, Joel; Flynn, Patrick J; Erlichman, Charles

2012-05-01

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. Copyright © 2011 American Cancer Society.

Phase 2 Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer

PubMed Central

Philip, Philip A.; Mahoney, Michelle R.; Holen, Kyle D.; Northfelt, Donald W.; Pitot, Henry C.; Picus, Joel; Flynn, Patrick J.; Erlichman, Charles

2013-01-01

BACKGROUND Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). METHODS Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child’s Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. RESULTS Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child’s A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. CONCLUSIONS In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. PMID:21953248

Proteomic Signatures of Acquired Letrozole Resistance in Breast Cancer: Suppressed Estrogen Signaling and Increased Cell Motility and Invasiveness*

PubMed Central

Tilghman, Syreeta L.; Townley, Ian; Zhong, Qiu; Carriere, Patrick P.; Zou, Jin; Llopis, Shawn D.; Preyan, Lynez C.; Williams, Christopher C.; Skripnikova, Elena; Bratton, Melyssa R.; Zhang, Qiang; Wang, Guangdi

2013-01-01

Aromatase inhibitors, such as letrozole, have become the first-line treatment for postmenopausal women with estrogen-dependent breast cancer. However, acquired resistance remains a major clinical obstacle. Previous studies demonstrated constitutive activation of the MAPK signaling, overexpression of HER2, and down-regulation of aromatase and ERα in letrozole-resistant breast cancer cells. Given the complex signaling network involved in letrozole-refractory breast cancer and the lack of effective treatment for hormone resistance, further investigation of aromatase inhibitor resistance by a novel systems biology approach may reveal previously unconsidered molecular changes that could be utilized as therapeutic targets. This study was undertaken to characterize for the first time global proteomic alterations occurring in a letrozole-resistant cell line. A quantitative proteomic analysis of the whole cell lysates of LTLT-Ca (resistant) versus AC-1 cells (sensitive) was performed to identify significant protein expression changes. A total of 1743 proteins were identified and quantified, of which 411 were significantly up-regulated and 452 significantly down-regulated (p < 0.05, fold change > 1.20). Bioinformatics analysis revealed that acquired letrozole resistance is associated with a hormone-independent, more aggressive phenotype. LTLT-Ca cells exhibited 84% and 138% increase in migration and invasion compared with the control cells. The ROCK inhibitor partially abrogated the enhanced migration and invasion of the letrozole-resistant cells. Flow cytometric analyses also demonstrated an increase in vimentin and twist expression in letrozole-resistance cells, suggesting an onset of epithelial to mesenchymal transition (EMT). Moreover, targeted gene expression arrays confirmed a 28-fold and sixfold up-regulation of EGFR and HER2, respectively, whereas ERα and pS2 were dramatically reduced by 28-fold and 1100-fold, respectively. Taken together, our study revealed global

Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance.

PubMed

Bagchi, Atrish; Haidar, Jaafar N; Eastman, Scott W; Vieth, Michal; Topper, Michael; Iacolina, Michelle D; Walker, Jason M; Forest, Amelie; Shen, Yang; Novosiadly, Ruslan D; Ferguson, Kathryn M

2018-02-01

Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 Å resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab-resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. Mol Cancer Ther; 17(2); 521-31. ©2017 AACR . ©2017 American Association for Cancer Research.

A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS).

PubMed

Smit, Egbert F; Wu, Yi-Long; Gervais, Radj; Zhou, Caicun; Felip, Enriqueta; Feng, Jifeng; Guclu, Salih Zeki; Hoiczyk, Mathias; Dorokhova, Elena; Freudensprung, Ulrich; Grange, Susan; Perez-Moreno, Pablo Diego; Mitchell, Lada; Reck, Martin

2016-09-01

Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150mg dose (E150). Patients with stage IIIB/IV NSCLC (current smokers who failed first-line platinum-based chemotherapy) were randomized to receive E150 or E300 until progression/death/unacceptable toxicity. progression-free survival (PFS). Secondary endpoints: overall survival (OS), disease control rate and safety. A total of 342 patients were screened; the intent-to-treat population comprised 159 E300 patients and 154 E150 patients. Median PFS was 7.0 versus 6.9 weeks with E300 versus E150, respectively (unstratified hazard ratio [HR]=1.05, 95% confidence interval [CI]: 0.83-1.33; unstratified log-rank P=0.671). Median OS was 6.8 months in both arms (unstratified HR=1.03, 95% CI: 0.80-1.32; unstratified log-rank P=0.846). Overall, 89.2% (E300 arm) and 84.4% (E150 arm) experienced ≥1 adverse event (AE) of any grade (44.3% and 37%, respectively, experienced grade ≥3 AEs); AEs of special interest were reported in 67.7% and 47.4% of patients, respectively. E300 resulted in higher mean plasma concentrations versus E150, however, this did not improve efficacy. Despite the difference in erlotinib exposure, there was no evidence of an incremental efficacy benefit of a higher erlotinib dose versus the standard dose in this population of highly active smokers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Serum metabolite profiles are altered by erlotinib treatment and the integrin α1-null genotype, but not by post traumatic osteoarthritis

PubMed Central

Mickiewicz, Beata; Shin, Sung Y.; Pozzi, Ambra; Vogel, Hans J.; Clark, Andrea L.

2016-01-01

The risk of developing post traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA, however the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following 1H nuclear magnetic resonance spectroscopy we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice, and the integrin α1-null versus wild type mouse genotype. Our results show the sex dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site specific factors such as surgery. PMID:26784366

Phase I/II Study of Erlotinib Combined With Cisplatin and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herchenhorn, Daniel, E-mail: herchenhorn@hotmail.co; Dias, Fernando L.; Viegas, Celia M.P.

Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m{sup 2} of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuingmore » during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.« less

Successful treatment with erlotinib of severe neutropenia induced by gefitinib in a patient with advanced non-small cell lung cancer.

PubMed

Araya, Tomoyuki; Kasahara, Kazuo; Demura, Yoshiki; Matsuoka, Hiroki; Nishitsuji, Masaru; Nishi, Koichi

2013-06-01

Neutropenia is a rare side effect of gefitinib and was scarcely reported in many large-scale randomized phase III trials using gefitinib monotherapy as first-line treatment. A 77-year-old female was referred to our institution due to abnormal shadow of the right lung, diagnosed by CT scan and biopsy histopathology as adenocarcinoma of the lung (cT3N1M1b). Mutation analysis with PCR-Invader assay of tumor DNA samples revealed short in-frame deletion in exon 19. Based on the diagnosis, first-line treatment was initiated using oral gefitinib (250 mg, daily). During the initial 27 days of gefitinib therapy, the only side effect was a mild skin rash. After 28 days, there was marked tumor shrinkage, indicative of a partial response to gefitinib; however, grade 4 neutropenia was also detected. The patient was switched to the oral erlotinib monotherapy (150 mg/day) as second-line chemotherapy with careful monitoring of neutropenia. Discontinuation of the gefitinib, without the need for granulocyte colony-stimulating factor support, was successful in allowing the neutrophils and leukocytes counts to recover to normal by day 47. The patient continued oral erlotinib for more than 9 months and there has been no evidence of neutropenia, leukopenia, or disease progression. Clinicians should be aware that gefitinib-induced neutropenia in patients with non-small cell lung cancer can be treated successful by switching to erlotinib. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report.

PubMed

Mody, Kabir; Strauss, Edward; Lincer, Robert; Frank, Richard C

2010-10-20

Gallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene. A 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine (1000 mg/m2) on day 1 and 8 every 21 days as well as daily erlotinib (100 mg). After four cycles of therapy, the CA 19-9 normalized and a PET/CT showed a complete remission; this response was maintained by the end of 12 cycles of therapy. Gemcitabine was then discontinued and single agent erlotinib was continued as maintenance therapy. The disease remains in good control 18 months after initiation of therapy, including 6 months on maintenance erlotinib. The only grade 3 toxicity was a typical EGFR-related skin rash. Because of the remarkable response to erlotinib plus gemcitabine, we performed tumor genotyping of the EGFR gene for response predicting mutations in exons 18, 19 and 21. This disclosed the wild-type genotype with no mutations found. This case report demonstrates a patient with stage IV gallbladder cancer who experienced a rarely encountered complete, prolonged response after treatment with an oral EGFR-TKI plus chemotherapy. This response occurred in the absence of an EGFR gene mutation. These observations should inform the design of clinical trials using EGFR-TKIs to treat gallbladder and other biliary tract cancers; such trials should not select patients based on EGFR mutation status.

FREEQUNCY OF ESCHERICHIA COLI IN PATIENTS WITH COMMUNITY ACQUIRED URINARY TRACT INFECTION AND THEIR RESISTANCE PATTERN AGAINST SOME COMMONLY USED ANTI BACTERIALS.

PubMed

Ahmad, Waseem; Jamshed, Fareeda; Ahmad, Wajeeha

2015-01-01

Urinary tract infection (UTI) is a very common health problem and Escherichia coli (E coli) are the most common organisms associated with community acquired UTI. Unfortunately these bacteria have developed extensive resistance against most of the commonly used antibacterials. The objective of this study was to determine the frequency and resistance pattern of E. Coli in patients of community acquired UTI in an area in northern part of Pakistan. Urine specimens were collected from patients who were clinically diagnosed as community acquired UTI. Urine routine examination (Urine RE) was done and samples positive for UTI (Pus cells >10/High Power Field) were included in the study. These samples were inoculated on Eosin Methylene Blue (EMB) agar plates and incubated at 37 degrees C for 36 hours. Suspected colonies were then inoculated further on EMB plates for pure cultures of E. Coli characterized by certain morphological characteristics. IMViC was applied for the confirmation of E coli. In vitro antibiotic susceptibility tests of E. Coli were performed with standardized commercial susceptibility discs (OXOID). Out of 50 specimens, positive for UTI by urine RE, 20 showed pure growth of E. Coli on culture (40%). The majority of the isolates (28%; n=14) were from women while only 12% (n=6) were from men. Escherichia coli showed a high rate of resistance towards Ampicillin (90%), Tetracycline (70%), Erythromycin (70%) and Trimethoprim-Sulfamethoxazole (55%). Sparfloxacin showed better results (45%) than ciprofloxacin (50%). Out of 20 E. Coli isolates, two (10%) were resistant to all the antibacterials except chloramphenicol, eight isolates (40%) showed resistance to six or more than six while 14 (70%) were resistant to four or more than four drugs. Rate of resistance of E. Coli against commonly used antibacterials was quite high and majority of the strains showed multidrug resistance.

Two novel ALK mutations mediate acquired resistance to the next generation ALK inhibitor alectinib

PubMed Central

Katayama, Ryohei; Friboulet, Luc; Koike, Sumie; Lockerman, Elizabeth L.; Khan, Tahsin M.; Gainor, Justin F.; Iafrate, A. John; Takeuchi, Kengo; Taiji, Makoto; Okuno, Yasushi; Fujita, Naoya; Engelman, Jeffrey A.; Shaw, Alice T.

2014-01-01

Purpose The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged NSCLC. Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. Experimental Design We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity-relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. Results We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. Conclusions We have identified two novel ALK mutations arising after alectinib exposure which are sensitive to other next generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. PMID:25228534

Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.

PubMed

Katayama, Ryohei; Friboulet, Luc; Koike, Sumie; Lockerman, Elizabeth L; Khan, Tahsin M; Gainor, Justin F; Iafrate, A John; Takeuchi, Kengo; Taiji, Makoto; Okuno, Yasushi; Fujita, Naoya; Engelman, Jeffrey A; Shaw, Alice T

2014-11-15

The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. ©2014 American Association for Cancer Research.

Naturally occurring dominant drug resistance mutations occur infrequently in the setting of recently acquired hepatitis C.

PubMed

Applegate, Tanya L; Gaudieri, Silvana; Plauzolles, Anne; Chopra, Abha; Grebely, Jason; Lucas, Michaela; Hellard, Margaret; Luciani, Fabio; Dore, Gregory J; Matthews, Gail V

2015-01-01

Direct-acting antivirals (DAAs) are predicted to transform hepatitis C therapy, yet little is known about the prevalence of naturally occurring resistance mutations in recently acquired HCV. This study aimed to determine the prevalence and frequency of drug resistance mutations in the viral quasispecies among HIV-positive and -negative individuals with recent HCV. The NS3 protease, NS5A and NS5B polymerase genes were amplified from 50 genotype 1a participants of the Australian Trial in Acute Hepatitis C. Amino acid variations at sites known to be associated with possible drug resistance were analysed by ultra-deep pyrosequencing. A total of 12% of individuals harboured dominant resistance mutations, while 36% demonstrated non-dominant resistant variants below that detectable by bulk sequencing (that is, <20%) but above a threshold of 1%. Resistance variants (<1%) were observed at most sites associated with DAA resistance from all classes, with the exception of sofosbuvir. Dominant resistant mutations were uncommonly observed in the setting of recent HCV. However, low-level mutations to all DAA classes were observed by deep sequencing at the majority of sites and in most individuals. The significance of these variants and impact on future treatment options remains to be determined. Clinicaltrials.gov NCT00192569.

Antibiotic Exposure in the Community and Resistance Patterns of Escherichia coli Community-Acquired Bloodstream Infection.

PubMed

Gottesman, Bat-Sheva; Shitrit, Pnina; Katzir, Michal; Chowers, Michal

2018-06-01

Increasing antibiotic resistance in the community results in greater use of empiric broad spectrum antibiotics for patients at hospital admission. As a measure of antibiotic stewardship it is important to identify a patient population that can receive narrow spectrum antibiotics. To evaluate resistance patterns of Escherichia coli bloodstream infection (BSI) from strictly community-acquired infection and the impact of recent antibiotic use on this resistance. This single center, historical cohort study of adult patients with E. coli BSI was conducted from January 2007 to December 2011. Patients had no exposure to any healthcare facility and no chronic catheters or chronic ulcers. Data on antibiotic use during the previous 90 days was collected and relation to resistance patterns was assessed. Of the total number of patients, 267 BSI cases met the entry criteria; 153 patients (57%) had bacteria sensitive to all antibiotics. Among 189 patients with no antibiotic exposure, 61% of isolates (116) were pan-sensitive. Resistance to any antibiotic appeared in 114 patients and 12 were extended-spectrum beta-lactamase (ESBL) producers. Quinolone use was the main driver of resistance to any antibiotic and to ESBL resistance patterns. In a multivariate analysis, older age (odds ratio 1.1) and quinolone use (odds ratio 7) were independently correlated to ESBL. At admission, stratification by patient characteristics and recent antibiotic use can help personalize primary empirical therapy.

Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells

PubMed Central

Bodo, Juraj; Zhao, Xiaoxian; Durkin, Lisa; Souers, Andrew J.; Phillips, Darren C.; Smith, Mitchell R.; Hsi, Eric D.

2016-01-01

The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL. The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed. The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients. PMID:27661108

Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells.

PubMed

Bodo, Juraj; Zhao, Xiaoxian; Durkin, Lisa; Souers, Andrew J; Phillips, Darren C; Smith, Mitchell R; Hsi, Eric D

2016-10-25

The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/ BIM complex and a decrease in mitochondrial potential. Interestingly the population of cells that survived venetoclax treatment showed increased p-ERK1/2 and p-BIM (S69), as well as a decrease in total BIM levels. Venetoclax resistant cells initially showed elevated levels of p-AKT and p-Foxo1/3a, a dissociation of BIM/BCL-2/BECLIN1 complex, and a decrease in SQSTM1/p62 level (indicating increased autophagy) together with a slight decline in BIM expression. After stable resistant cell lines were established, a significant reduction of BCL-2 levels and almost total absence of BIM was observed.The acquisition of these resistance phenotypes could be prevented via selective ERK/AKT inhibition or anti-CD20 antibody treatment, thus highlighting possible combination therapies for FL patients.

Systemic acquired resistance: turning local infection into global defense.

PubMed

Fu, Zheng Qing; Dong, Xinnian

2013-01-01

Systemic acquired resistance (SAR) is an induced immune mechanism in plants. Unlike vertebrate adaptive immunity, SAR is broad spectrum, with no specificity to the initial infection. An avirulent pathogen causing local programmed cell death can induce SAR through generation of mobile signals, accumulation of the defense hormone salicylic acid, and secretion of the antimicrobial PR (pathogenesis-related) proteins. Consequently, the rest of the plant is protected from secondary infection for a period of weeks to months. SAR can even be passed on to progeny through epigenetic regulation. The Arabidopsis NPR1 (nonexpresser of PR genes 1) protein is a master regulator of SAR. Recent study has shown that salicylic acid directly binds to the NPR1 adaptor proteins NPR3 and NPR4, regulates their interactions with NPR1, and controls NPR1 protein stability. However, how NPR1 interacts with TGA transcription factors to activate defense gene expression is still not well understood. In addition, redox regulators, the mediator complex, WRKY transcription factors, endoplasmic reticulum-resident proteins, and DNA repair proteins play critical roles in SAR.

Synergistic Combination of Novel Tubulin Inhibitor ABI-274 and Vemurafenib Overcome Vemurafenib Acquired Resistance in BRAFV600E Melanoma

PubMed Central

Wang, Jin; Chen, Jianjun; Miller, Duane D.; Li, Wei

2013-01-01

Acquired clinical resistance to vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short term chemotherapy. Since inhibitions of targets in the RAF-MEK-ERK pathway result in G0/G1 cell cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in G1/G2/M phase, and significantly increased apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of ERK phosphorylation. Finally, in vivo co-administration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current vemurafenib therapy. PMID:24249714

An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma.

PubMed

Lamhamedi-Cherradi, Salah-Eddine; Menegaz, Brian A; Ramamoorthy, Vandhana; Aiyer, Ramani A; Maywald, Rebecca L; Buford, Adrianna S; Doolittle, Dannette K; Culotta, Kirk S; O'Dorisio, James E; Ludwig, Joseph A

2015-07-01

Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. ©2015 American Association for Cancer Research.

Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers

PubMed Central

Essenburg, Curt J.; Turner, Lisa; Madaj, Zachary; Winn, Mary E.; Melnik, Marianne K.; Korkaya, Hasan; Maroun, Christiane R.; Christensen, James G.; Steensma, Matthew R.; Boerner, Julie L.; Graveel, Carrie R.

2016-01-01

There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients. PMID:27655711

Antibiotic Resistance, Virulence, and Genetic Background of Community-Acquired Uropathogenic Escherichia coli from Algeria.

PubMed

Yahiaoui, Merzouk; Robin, Frédéric; Bakour, Rabah; Hamidi, Moufida; Bonnet, Richard; Messai, Yamina

2015-10-01

The aim of the study was to investigate antibiotic resistance mechanisms, virulence traits, and genetic background of 150 nonrepetitive community-acquired uropathogenic Escherichia coli (CA-UPEC) from Algeria. A rate of 46.7% of isolates was multidrug resistant. bla genes detected were blaTEM (96.8% of amoxicillin-resistant isolates), blaCTX-M-15 (4%), overexpressed blaAmpC (4%), blaSHV-2a, blaTEM-4, blaTEM-31, and blaTEM-35 (0.7%). All tetracycline-resistant isolates (51.3%) had tetA and/or tetB genes. Sulfonamides and trimethoprim resistance genes were sul2 (60.8%), sul1 (45.9%), sul3 (6.7%), dfrA14 (25.4%), dfrA1 (18.2%), dfrA12 (16.3%), and dfrA25 (5.4%). High-level fluoroquinolone resistance (22.7%) was mediated by mutations in gyrA (S83L-D87N) and parC (S80I-E84G/V or S80I) genes. qnrB5, qnrS1, and aac(6')-Ib-cr were rare (5.3%). Class 1 and/or class 2 integrons were detected (40.7%). Isolates belonged to phylogroups B2+D (50%), A+B1 (36%), and F+C+Clade I (13%). Most of D (72.2%) and 38.6% of B2 isolates were multidrug resistant; they belong to 14 different sequence types, including international successful ST131, ST73, and ST69, reported for the first time in the community in Algeria and new ST4494 and ST4529 described in this study. Besides multidrug resistance, B2 and D isolates possessed virulence factors of colonization, invasion, and long-term persistence. The study highlighted multidrug-resistant CA-UPEC with high virulence traits and an epidemic genetic background.

Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells.

PubMed

Filosto, Simone; Baston, David S; Chung, Samuel; Becker, Cathleen R; Goldkorn, Tzipora

2013-08-01

The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non-small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke-induced resistance to TKIs in both WT EGFR- and L858R MT EGFR-expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke-exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke-exposed L858R EGFR-expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers.

Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells

PubMed Central

Filosto, Simone; Baston, David S.; Chung, Samuel; Becker, Cathleen R.; Goldkorn, Tzipora

2015-01-01

The EGF Receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non-small cell lung cancer (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKIs) such as Erlotinib. However, despite the efficacy observed in NSCLC patients harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in NSCLC patients who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke (CS), evidenced by their auto-phosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating CS-induced resistance to TKIs in both WT EGFR and L858R MT EGFR expressing NSCLC cells. First, we show that CS exposure of A549 cells leads to time-dependent activation of Src which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we demonstrate that Src inhibition restores TKI sensitivity in CS-exposed NSCLC cells, preventing EGFR auto-phosphorylation in the presence of Erlotinib. Furthermore, we show that over-expression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to CS. Importantly, the TKI resistance that emerges even in CS-exposed L858R EGFR expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers. PMID:23686837

Community-acquired methicillin-resistant Staphylococcus aureus can persist in the throat.

PubMed

Hamdan-Partida, Aida; González-García, Samuel; de la Rosa García, Estela; Bustos-Martínez, Jaime

2018-06-01

Colonization by Staphylococcus aureus is an important factor in infections caused by this microorganism. Among the colonization niches of staphylococci are the nose, skin, intestinal tract, and, recently, the throat has been given relevance. Infections caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) can be fatal. Persistence of S. aureus is an important process in the pathogenesis of this microorganism and must be studied. The aim of this study was to determine the persistence of S. aureus in the throat, and characterized the strains. We studied the persistence of S. aureus for 6 years in the throat of apparently healthy people. The isolated strains from the persistent carriers were characterized through PFGE, spa-typing, SCCmec typing, resistance to methicillin, presence of virulence genes (adhesins and toxins), and the formation of biofilm. We found persistent and intermittent carriers of S. aureus in the throat, with methicillin-sensitive (MSSA), methicillin-resistant (MRSA) strains, and confirmed for the first time that CA-MRSA colonizes this niche. These strains can colonize persistently the throat for four years or more. Typification of strains through PFGE and spa-typing revealed that some carriers present the same strain, whereas others present different strains along the period of persistence. Almost all strains induced a strong biofilm formation. All strains presented adhesin and toxin genes, but no shared genotype was found. We conclude that S. aureus, including CA-MRSA strains, can remain persistently in the throat, finding a wide variability among the persistent strains. Copyright © 2018 Elsevier GmbH. All rights reserved.

Tumor marker analyses from the phase III, placebo-controlled, FASTACT-2 study of intercalated erlotinib with gemcitabine/platinum in the first-line treatment of advanced non-small-cell lung cancer.

PubMed

Mok, Tony; Ladrera, Guia; Srimuninnimit, Vichien; Sriuranpong, Virote; Yu, Chong-Jen; Thongprasert, Sumitra; Sandoval-Tan, Jennifer; Lee, Jin Soo; Fuerte, Fatima; Shames, David S; Klughammer, Barbara; Truman, Matt; Perez-Moreno, Pablo; Wu, Yi-Long

2016-08-01

The FASTACT-2 study of intercalated erlotinib with chemotherapy in Asian patients found that EGFR mutations were the main driver behind the significant progression-free survival (PFS) benefit noted in the overall population. Further exploratory biomarker analyses were conducted to provide additional insight. This multicenter, randomized, placebo-controlled, double-blind, phase III study investigated intercalated first-line erlotinib or placebo with gemcitabine/platinum, followed by maintenance erlotinib or placebo, for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Provision of samples for biomarker analysis was encouraged but not mandatory. The following biomarkers were analyzed (in order of priority): EGFR mutation by cobas(®) test, KRAS mutation by cobas(®)KRAS test, HER2 by immunohistochemistry (IHC), HER3 by IHC, ERCC1 by IHC, EGFR gene copy number by fluorescence in-situ hybridization (FISH) and EGFR by IHC. All subgroups were assessed for PFS (primary endpoint), overall survival (OS), non-progression rate and objective response rate. Overall, 256 patients provided samples for analysis. Considerable overlap was noted among biomarkers, except for EGFR and KRAS mutations, which are mutually exclusive. Other than EGFR mutations (p<0.0001), no other biomarkers were significantly predictive of outcomes in a treatment-by-biomarker interaction test, although ERCC1 IHC-positive status was predictive of improved OS for the erlotinib arm versus placebo in EGFR wild-type patients (median 18.4 vs 9.5 months; hazard ratio [HR] HR=0.32, 95% confidence intervals [CI]: 0.14-0.69, p=0.0024). Activating EGFR mutations were predictive for improved treatment outcomes with a first-line intercalated regimen of chemotherapy and erlotinib in NSCLC. ERCC1 status may have some predictive value in EGFR wild-type disease, but requires further investigation. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and Erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis.

PubMed

Olmez, Inan; Donahue, Bernadine R; Butler, James S; Huang, Yiwu; Rubin, Philip; Xu, Yiqing

2010-11-01

Thirty percent of newly diagnosed NSCLC patients present with synchronous brain metastases, most of whom are treated with whole brain radiation. Systemic chemotherapy is usually avoided during WBRT due to concerns regarding toxicity. However, concurrent administration of targeted agents, such as Erlotinib, during WBRT may address systemic disease without causing toxicity. We report our institutional data on outcomes and toxicities with this treatment approach. Medical records of patients with newly diagnosed NSCLC and brain metastases receiving concurrent WBRT and Erlotinib treatment were reviewed. Radiographic response to therapy and toxicities were analyzed. Eight patients were identified and 7 were evaluable for response. All patients had intracranial disease control. In the extracranial sites, 3 (37.5%, intent-to-treat) showed partial response (PR), 2 (25%) had stable disease (SD), 1 (12.5%) had progression (PD) and 1 (12.5%) had new air space disease obscuring tumor response assessment. Among the three responders, two were female never smokers, while one was a female current smoker. Unanticipated grade 3 hepatotoxitity, hyponatremia, mental status changes, grade 3 and 4 thrombocytopenia, and grade 4 neutropenia with sepsis were observed. Three deaths occurred without clear signs of disease progression: one from neutropenic sepsis, one from wide spread air space disease, and one from neurologic deterioration. Our data demonstrates a high percentage of extracranial tumor response rates with first line Erlotinib in selected NSCLC patients. We observed unexpected serious complications and postulate possible mechanisms. We recommend caution to be exercised when considering Erlotinib treatment during WBRT, particularly in regard to drug-drug interactions and infection control. Data from prospective trials are needed to determine the benefits and toxicities of Erlotinib during WBRT. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Travel to Asia and traveller's diarrhoea with antibiotic treatment are independent risk factors for acquiring ciprofloxacin-resistant and extended spectrum β-lactamase-producing Enterobacteriaceae-a prospective cohort study.

PubMed

Reuland, E A; Sonder, G J B; Stolte, I; Al Naiemi, N; Koek, A; Linde, G B; van de Laar, T J W; Vandenbroucke-Grauls, C M J E; van Dam, A P

2016-08-01

Travel to (sub)tropical countries is a well-known risk factor for acquiring resistant bacterial strains, which is especially of significance for travellers from countries with low resistance rates. In this study we investigated the rate of and risk factors for travel-related acquisition of extended spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E), ciprofloxacin-resistant Enterobacteriaceae (CIPR-E) and carbapenem-resistant Enterobacteriaceae. Data before and after travel were collected from 445 participants. Swabs were cultured with an enrichment broth and sub-cultured on selective agar plates for ESBL detection, and on plates with a ciprofloxacin disc. ESBL production was confirmed with the double-disc synergy test. Species identification and susceptibility testing were performed with the Vitek-2 system. All isolates were subjected to ertapenem Etest. ESBL and carbapenemase genes were characterized by PCR and sequencing. Twenty-seven out of 445 travellers (6.1%) already had ESBL-producing strains and 45 of 445 (10.1%) travellers had strains resistant to ciprofloxacin before travel. Ninety-eight out of 418 (23.4%) travellers acquired ESBL-E and 130 of 400 (32.5%) travellers acquired a ciprofloxacin-resistant strain. Of the 98 ESBL-E, predominantly Escherichia coli and predominantly blaCTX-M-15, 56% (55/98) were resistant to gentamicin, ciprofloxacin and co-trimoxazole. Multivariate analysis showed that Asia was a high-risk area for ESBL-E as well as CIPR-E acquisition. Travellers with diarrhoea combined with antimicrobial use were significantly at higher risk for acquisition of resistant strains. Only one carbapenemase-producing isolate was acquired, isolated from a participant after visiting Egypt. In conclusion, travelling to Asia and diarrhoea combined with antimicrobial use are important risk factors for acquiring ESBL-E and CIPR-E. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All

Antimicrobial-resistant Pseudomonas aeruginosa and Acinetobacter baumannii From Patients With Hospital-acquired or Ventilator-associated Pneumonia in Vietnam.

PubMed

Biedenbach, Douglas J; Giao, Phan Trong; Hung Van, Pham; Su Minh Tuyet, Nguyen; Thi Thanh Nga, Tran; Phuong, Doan Mai; Vu Trung, Nguyen; Badal, Robert E

2016-09-01

Multidrug-resistant bacterial pathogens are becoming a significant problem worldwide. Acinetobacter baumannii and Pseudomonas aeruginosa are problematic multidrug-resistant pathogens. This multicenter study in Vietnam determined the level of resistance to antimicrobial agents used to treat A baumannii and P aeruginosa infections in this country. Five medical centers in Vietnam provided 529 P aeruginosa and 971 Acinetobacter species (904 A baumannii) isolates from patients with hospital-acquired or ventilator-associated pneumonia from 2012 to 2014. A central laboratory verified identification of the isolates and performed susceptibility testing using Clinical and Laboratory Standards Institute methods. Resistance to cephalosporins, β-lactam/β-lactamase inhibitors, carbapenems, and fluoroquinolones was >90% against A baumannii. Aminoglycosides had only slightly better activity, with amikacin resistance >80%. Only colistin (MIC90, ≤0.25 mg/L) and tigecycline (MIC90, 4 mg/L) had appreciable activity against A baumannii. Similar activity was observed among the β-lactams tested against P aeruginosa. Cefepime demonstrated the highest activity (60.1% susceptible), which was similar to doripenem (58.6% susceptible), the most active carbapenem tested. Amikacin was the most active aminoglycoside tested against P aeruginosa, with susceptibility of 81.7% compared with tobramycin (58.0%) and gentamicin (56.5%). Fluoroquinolones had limited activity against P aeruginosa with susceptibility to ciprofloxacin (55.0%). All P aeruginosa isolates had colistin MIC values ≤2 mg/L. The data from this 3-year longitudinal study in Vietnam demonstrate that 2 of the most common nonfermentative gram-negative pathogens associated with hospital-acquired and ventilator-associated pneumonia are significantly resistant to most of the available treatment options and require combination therapies unless new antimicrobial agents become available. Copyright © 2016. Published by Elsevier Inc.

ESR1 mutations as a mechanism for acquired endocrine resistance in breast cancer

PubMed Central

Jeselsohn, Rinath; Buchwalter, Gilles; De Angelis, Carmine; Brown, Myles; Schiff, Rachel

2016-01-01

Most breast cancers are estrogen receptor α (ER)-positive (+) and are treated with endocrine therapies targeting ER activity. Despite efforts, the mechanisms of the frequent clinical resistance to these therapies remain largely unknown. Several recent parallel studies unveiled gain-of-function recurrent ESR1 mutations in up to 20% of patients with metastatic ER+ disease who all received endocrine therapies, which for more cases included an aromatase inhibitor. These mutations, clustered in a hotspot within the ligand-binding domain (LBD), lead to ligand independent ER activity and tumor growth, partial resistance to tamoxifen and fulvestrant, and potentially increased metastatic capacity. Together, these findings suggest that the ESR1 LBD mutations account for acquired endocrine resistance in a substantial fraction of patients with metastatic disease. The absence of detectable ESR1 mutations in treatment-naïve disease and the correlation with the number of endocrine treatments indicate a clonal expansion of rare mutant clones, selected under the pressure of treatment. New technologies to detect low/ultra rare ESR1 mutations together with tissue and liquid biopsies are required to fully expose their clinical relevance in prognosis and treatment. Pre-clinical and clinical development of rationale-based novel therapeutic strategies to inhibit these mutants has the potential to substantially improve treatment outcomes. PMID:26122181

A horizontally gene transferred copper resistance locus confers hyper‐resistance to antibacterial copper toxicity and enables survival of community acquired methicillin resistant Staphylococcus aureus USA300 in macrophages

PubMed Central

Purves, Joanne; Thomas, Jamie; Riboldi, Gustavo P.; Zapotoczna, Marta; Tarrant, Emma; Andrew, Peter W.; Londoño, Alejandra; Planet, Paul J.; Geoghegan, Joan A.; Waldron, Kevin J.

2018-01-01

Summary Excess copper is highly toxic and forms part of the host innate immune system's antibacterial arsenal, accumulating at sites of infection and acting within macrophages to kill engulfed pathogens. We show for the first time that a novel, horizontally gene transferred copper resistance locus (copXL), uniquely associated with the SCCmec elements of the highly virulent, epidemic, community acquired methicillin resistant Staphylococcus aureus (CA‐MRSA) USA300, confers copper hyper‐resistance. These genes are additional to existing core genome copper resistance mechanisms, and are not found in typical S. aureus lineages, but are increasingly identified in emerging pathogenic isolates. Our data show that CopX, a putative P1B‐3‐ATPase efflux transporter, and CopL, a novel lipoprotein, confer copper hyper‐resistance compared to typical S. aureus strains. The copXL genes form an operon that is tightly repressed in low copper environments by the copper regulator CsoR. Significantly, CopX and CopL are important for S. aureus USA300 intracellular survival within macrophages. Therefore, the emergence of new S. aureus clones with the copXL locus has significant implications for public health because these genes confer increased resistance to antibacterial copper toxicity, enhancing bacterial fitness by altering S. aureus interaction with innate immunity. PMID:29521441

Community-acquired methicillin-resistant Staphylococcus aureus among patients with puerperal mastitis requiring hospitalization.

PubMed

Stafford, Irene; Hernandez, Jennifer; Laibl, Vanessa; Sheffield, Jeanne; Roberts, Scott; Wendel, George

2008-09-01

To estimate the incidence of puerperal mastitis requiring hospital admission and to describe demographic and obstetric risk factors for this condition. We also sought to identify trends in bacteriology among isolates obtained from breast abscesses and breast-milk aspirates, with a focus on treatment strategies used for community-acquired methicillin-resistant Staphylococcus aureus (MRSA). Patients with puerperal mastitis who were admitted to a county-based teaching hospital between January 1997 and December 2005 were identified by International Classification of Diseases, 9th Revision, codes (675.1, 675.2). Data collected included demographic characteristics, clinical presentation, treatment, duration of admission, premorbid antibiotic exposure, and bacteriology. Demographic variables and obstetric outcomes were compared with all other pregnant women delivered at our hospital. One hundred twenty-seven of 136,459 women delivered at our teaching hospital were admitted for puerperal mastitis (9.3 [95% confidence interval (CI) 7.8-11.1] per 10,000 deliveries). The incidence of mastitis only during the study period was 6.7 (95% CI 5.4-8.3) per 10,000 deliveries, and the incidence of mastitis with breast abscess was 2.6 (95% CI 1.8-3.6) per 10,000 deliveries. Puerperal mastitis was significantly associated with younger women (23.4 years compared with 25.1 years, P<.001) and decreased parity (P=.02). Clinically significant breast abscess (n=35, 28%) was seen most commonly with community-acquired MRSA (n=18, 67%) during the data-collection period. The majority (15 [56%]) of women with culture-proven MRSA did not receive antibiotic therapy to which this organism was sensitive. They were discharged without complication, and there were no treatment failures. Community-acquired MRSA was most commonly associated with breast abscess. The empiric use of antibiotics ineffective against community-acquired MRSA did not adversely affect the outcomes in this study.

Prevalence of and risk factors for community-acquired methicillin-resistant and methicillin-sensitive staphylococcus aureus colonization in children seen in a practice-based research network.

PubMed

Fritz, Stephanie A; Garbutt, Jane; Elward, Alexis; Shannon, William; Storch, Gregory A

2008-06-01

We sought to define the prevalence of and risk factors for methicillin-resistant Staphylococcus aureus nasal colonization in the St Louis pediatric population. Children from birth to 18 years of age presenting for sick and well visits were recruited from pediatric practices affiliated with a practice-based research network. Nasal swabs were obtained, and a questionnaire was administered. We enrolled 1300 participants from 11 practices. The prevalence of methicillin-resistant S aureus nasal colonization varied according to practice, from 0% to 9% (mean: 2.6%). The estimated population prevalence of methicillin-resistant S aureus nasal colonization for the 2 main counties of the St Louis metropolitan area was 2.4%. Of the 32 methicillin-resistant S aureus isolates, 9 (28%) were health care-associated types and 21 (66%) were community-acquired types. A significantly greater number of children with community-acquired methicillin-resistant S aureus were black and were enrolled in Medicaid, in comparison with children colonized with health care-associated methicillin-resistant S aureus. Children with both types of methicillin-resistant S aureus colonization had increased contact with health care, compared with children without colonization. Methicillin-sensitive S aureus nasal colonization ranged from 9% to 31% among practices (mean: 24%). The estimated population prevalence of methicillin-sensitive S aureus was 24.6%. Risk factors associated with methicillin-sensitive S aureus colonization included pet ownership, fingernail biting, and sports participation. Methicillin-resistant S aureus colonization is widespread among children in our community and includes strains associated with health care-associated and community-acquired infections.

Origin and Evolution of European Community-Acquired Methicillin-Resistant Staphylococcus aureus

PubMed Central

Wirth, Thierry; Andersen, Paal S.; Skov, Robert L.; De Grassi, Anna; Simões, Patricia Martins; Tristan, Anne; Petersen, Andreas; Aziz, Maliha; Kiil, Kristoffer; Cirković, Ivana; Udo, Edet E.; del Campo, Rosa; Vuopio-Varkila, Jaana; Ahmad, Norazah; Tokajian, Sima; Peters, Georg; Schaumburg, Frieder; Olsson-Liljequist, Barbro; Givskov, Michael; Driebe, Elizabeth E.; Vigh, Henrik E.; Shittu, Adebayo; Ramdani-Bougessa, Nadjia; Rasigade, Jean-Philippe; Price, Lance B.; Vandenesch, Francois; Larsen, Anders R.; Laurent, Frederic

2014-01-01

ABSTRACT Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations. PMID:25161186

Disseminated cryptococcosis and fluconazole resistant oral candidiasis in a patient with acquired immunodeficiency syndrome (AIDS).

PubMed

Kothavade, Rajendra J; Oberai, Chetan M; Valand, Arvind G; Panthaki, Mehroo H

2010-10-28

Disseminated cryptococcosis and recurrent oral candidiasis was presented in a-heterosexual AIDS patient. Candida tropicalis (C.tropicalis) was isolated from the oral pseudomembranous plaques and Cryptococcus neoformans (C. neoformans) was isolated from maculopapular lesions on body parts (face, hands and chest) and body fluids (urine, expectorated sputum, and cerebrospinal fluid). In vitro drug susceptibility testing on the yeast isolates demonstrated resistance to fluconazole acquired by C. tropicalis which was a suggestive possible root cause of recurrent oral candidiasis in this patient.

Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation

PubMed Central

2013-01-01

Background Astrocytes respond to local insults within the brain and the spinal cord with important changes in their phenotype. This process, overall known as “activation”, is observed upon proinflammatory stimulation and leads astrocytes to acquire either a detrimental phenotype, thereby contributing to the neurodegenerative process, or a protective phenotype, thus supporting neuronal survival. Within the mechanisms responsible for inflammatory neurodegeneration, oxidative stress plays a major role and has recently been recognized to be heavily influenced by changes in cytosolic iron levels. In this work, we investigated how activation affects the competence of astrocytes to handle iron overload and the ensuing oxidative stress. Methods Cultures of pure cortical astrocytes were preincubated with proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) or conditioned medium from lipopolysaccharide-activated microglia to promote activation and then exposed to a protocol of iron overload. Results We demonstrate that activated astrocytes display an efficient protection against iron-mediated oxidative stress and cell death. Based on this evidence, we performed a comprehensive biochemical and molecular analysis, including a transcriptomic approach, to identify the molecular basis of this resistance. Conclusions We propose the protective phenotype acquired after activation not to involve the most common astrocytic antioxidant pathway, based on the Nrf2 transcription factor, but to result from a complex change in the expression and activity of several genes involved in the control of cellular redox state. PMID:24160637

Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma

PubMed Central

Fedorenko, Inna V.; Paraiso, Kim H. T.; Smalley, Keiran S. M.

2014-01-01

The discovery of activating BRAF V600E mutations in 50% of all cutaneous melanomas has revolutionized the understanding of melanoma biology and provided new strategies for the therapeutic management of this deadly disease. Highly potent small molecule inhibitors of BRAF are now showing great promise as a novel therapeutic strategy for melanomas harboring activating BRAF V600E mutations and are associated with high levels of response. This commentary article discusses the latest data on the role of mutated BRAF in the development and progression of melanoma as the basis for understanding the mechanism of action of BRAF inhibitors in the preclinical and clinical settings. We further address the issue of BRAF inhibitor resistance and outline the latest insights into the mechanisms of therapeutic escape as well as describing approaches to prevent and abrogate the onset of both intrinsic and acquired drug resistance. It is likely that our evolving understanding of melanoma genetics and signaling will allow for the further personalization of melanoma therapy with the goal of improving clinical responses. PMID:21635872

Community-Acquired Methicillin-Resistant Staphylococcus aureus: The New Face of an Old Foe?

PubMed Central

Udo, Edet E.

2013-01-01

The burden of infections caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is increasing among different patient populations globally. As CA-MRSA has become established in healthcare facilities, the range of infections caused by them has also increased. Molecular characterization of CA-MRSA isolates obtained from different centers has revealed significant diversity in their genetic backgrounds. Although many CA-MRSA strains are still susceptible to non-β-lactam antibiotics, multiresistance to non-β-lactam agents has emerged in some clones, posing substantial problems for empirical and directed therapy of infections caused by these strains. Some CA-MRSA clones have acquired the capacity to spread locally and internationally. CA-MRSA belonging to ST80-MRSA-IV and ST30-MRSA-IV appear to be the dominant clones in the countries of the Gulf Cooperation Council (GCC). The emergence of pandemic CA-MRSA clones not only limits therapeutic options but also presents significant challenges for infection control. Continued monitoring of global epidemiology and emerging drug resistance data is critical for the effective management of these infections. PMID:24051949

Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kinsella, Paula, E-mail: paula.kinsella@dcu.ie; Howley, Rachel, E-mail: rhowley@rcsi.ie; Doolan, Padraig, E-mail: padraig.doolan@dcu.ie

2012-03-10

High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Responsemore » to TKIs was assessed using 50% inhibitory concentrations (IC{sub 50}). Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-{alpha} expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile. -- Highlights: Black-Right-Pointing-Pointer Non-responders had low EGFR expression, high PDGFR-{beta}, and a low proliferation rate. Black-Right-Pointing-Pointer PTEN is not indicative of response to a TKI. Black-Right-Pointing-Pointer Erlotinib response was not associated with expression of the proteins examined. Black-Right-Pointing-Pointer Imatinib-response correlated with expression of PDGFR-{alpha}. Black-Right-Pointing-Pointer Gefitinib response correlated with increased expression of EGFR.« less

Acquired resistance to rechallenge injury in rats recovered from subclinical renal damage with uranyl acetate-Importance of proliferative activity of tubular cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Yuan; Fujigaki, Yoshihide, E-mail: yf0516@hama-med.ac.j; Sakakima, Masanori

Animals recovered from acute renal failure are resistant to subsequent insult. We investigated whether rats recovered from mild proximal tubule (PT) injury without renal dysfunction (subclinical renal damage) acquire the same resistance. Rats 14 days after recovering from subclinical renal damage, which was induced by 0.2 mg/kg of uranyl acetate (UA) (sub-toxic dose), were rechallenged with 4 mg/kg of UA (nephrotoxic dose). Fate of PT cells and renal function were examined in response to nephrotoxic dose of UA. All divided cells after sub-toxic dose of UA insult were labeled with bromodeoxyuridine (BrdU) for 14 days then the number of PTmore » cells with or without BrdU-labeling was counted following nephrotoxic dose of UA insult. Rats recovered from subclinical renal damage gained resistance to nephrotoxic dose of UA with reduced renal dysfunction, less severity of peak damage (necrotic and TUNEL+ apoptotic cells) and accelerated PT cell proliferation, but with earlier peak of PT damage. The decrease in number of PT cells in the early phase of rechallenge injury with nephrotoxic UA was more in rats pretreated with sub-toxic dose of UA than vehicle pretreated rats. The exaggerated loss of PT cells was mainly caused by the exaggerated loss of BrdU+ divided cells. In contrast, accelerated cell proliferation in rats recovered from sub-toxic dose of UA was observed mainly in BrdU- non-divided cells. The findings suggest that rats recovered from subclinical renal damage showed partial acquired resistance to nephrotoxic insult. Accelerated recovery with increased proliferative activity of non-divided PT cells after subclinical renal damage may mainly contribute to acquired resistance.« less

Genetic diversity of Streptococcus suis isolated from three pig farms of China obtained by acquiring antibiotic resistance genes.

PubMed

Huang, Jinhu; Shang, Kexin; Kashif, Jam; Wang, Liping

2015-05-01

Acquiring antibiotic resistance genes may change an organism's genetic characteristics and the effect of antibiotics, resulting in a rapid transmission of microbial pathogens. The objectives of this experiment were to identify the features of Streptococcus suis (S. suis) isolated from three pig farms in China which are geographically isolated. Among the isolates, 56.52% were sequence type 7 (ST7), followed by ST1 (26.09%), indicating that ST7 prevails in China, as revealed by multi-locus sequence typing (MLST). Statistical analysis indicated an association between geography, sequence types and antibiotic resistance genotypes. 66.67% of the isolates in Sichuan province presented a (ermB(-) + mefA(-) + tetO(-) + tetM(-)) + ST7 type. The tetM(+) +ST7 type was the most prevalent in Jiangsu province, whereas the strains from Hebei province had a phenotype ermB(+) +tetO(+) +ST1 (63.64%). Pulsed-field gel electrophoresis (PGFE) pattern A2 with 100% similarity reflected the clonal dissemination between Sichuan and Jiangsu provinces. Strains carrying or not carrying antibiotic resistance genes presented different PFGE patterns in Hebei province. ST7 is widespread in many regions of China and a clonal dissemination occurred between Sichuan and Jiangsu provinces in diseased pigs. However, ST1 strains with macrolide and tetracycline resistance (ermB(+) +tetO(+) +ST1) isolated from a farm in Hebei province demonstrated that the genetic diversity was contributed by horizontal acquiring of ermB and tetO carrying elements. © 2014 Society of Chemical Industry.

Community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA)--a rare cause of fulminant orbital cellulitis.

PubMed

Shome, Debraj; Jain, Vandana; Natarajan, Sundaram; Agrawal, Shyam; Shah, Kiran

2008-01-01

We report a 55-year-old female patient who developed a severe right-sided orbital cellulitis. Past history was significant for a boil on the right upper eyelid 2 days prior. Visual acuity at presentation was perception of light with inaccurate projection. Orbital computed tomography (CT) scan and routine blood investigations, including blood culture, urine examination, and urine culture, were performed. CT scan showed a superonasal orbital mass suggestive of an abscess. Abscess drainage followed by pus culture, sensitivity, and pulsed-field gel electrophoresis revealed community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) resistant to all antibiotics except vancomycin, cotrimoxazole, and amikacin. The condition completely resolved post antibiotic and steroid therapy. At 3 months follow-up, the vision in the right eye was 6/9. We report this case to highlight CAMRSA as a rare but virulent cause of orbital cellulitis; empiric antibiotic therapy should include coverage for CAMRSA until susceptibilities come back.

The increasing importance of community-acquired methicillin-resistant Staphylococcus aureus infections.

PubMed

Agostino, Jason W; Ferguson, John K; Eastwood, Keith; Kirk, Martyn D

2017-11-06

To identify groups at risk of methicillin-resistant Staphylococcus aureus (MRSA) infection, patterns of antimicrobial resistance, and the proportion of patients with MRSA infections but no history of recent hospitalisation. Case series of 39 231 patients with S. aureus isolates from specimens processed by the Hunter New England Local Health District (HNELHD) public pathology provider during 2008-2014. Proportion of MRSA infections among people with S. aureus isolates; antimicrobial susceptibility of MRSA isolates; origin of MRSA infections (community- or health care-associated); demographic factors associated with community-associated MRSA infections. There were 71 736 S. aureus-positive specimens during the study period and MRSA was isolated from 19.3% of first positive specimens. Most patients (56.9%) from whom MRSA was isolated had not been admitted to a public hospital in the past year. Multiple regression identified that patients with community-associated MRSA were more likely to be younger (under 40), Indigenous Australians (odds ratio [OR], 2.6; 95% CI, 2.3-2.8), or a resident of an aged care facility (OR, 4.7; 95% CI, 3.8-5.8). The proportion of MRSA isolates that included the dominant multi-resistant strain (AUS-2/3-like) declined from 29.6% to 3.4% during the study period (P < 0.001), as did the rates of hospital origin MRSA in two of the major hospitals in the region. The prevalence of MRSA in the HNELHD region decreased during the study period, and was predominantly acquired in the community, particularly by young people, Indigenous Australians, and residents of aged care facilities. While the dominance of the multi-resistant strain decreased, new strategies for controlling infections in the community are needed to reduce the prevalence of non-multi-resistant strains.

Nanoparticulation improves bioavailability of Erlotinib.

PubMed

Yang, Kyung Mi; Shin, In Chul; Park, Joo Won; Kim, Kab-Sig; Kim, Dae Kyong; Park, Kyungmoon; Kim, Kunhong

2017-09-01

Nanoparticulation using fat and supercritical fluid (NUFS TM ) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS™ could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). NUFS-Ert was prepared using NUFS™ technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 °C, 4 °C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva ® . In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva ® . The relative bioavailability of NUFS-Ert compared with that of Tarceva ® was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva ® . NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva ® .

Update on the prevention and control of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA).

PubMed

Skov, Robert; Christiansen, Keryn; Dancer, Stephanie J; Daum, Robert S; Dryden, Matthew; Huang, Yhu-Chering; Lowy, Franklin D

2012-03-01

The rapid dissemination of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) since the early 2000s and the appearance of new successful lineages is a matter of concern. The burden of these infections varies widely between different groups of individuals and in different regions of the world. Estimating the total burden of disease is therefore problematic. Skin and soft-tissue infections, often in otherwise healthy young individuals, are the most common clinical manifestation of these infections. The antibiotic susceptibilities of these strains also vary, although they are often more susceptible to 'traditional' antibiotics than related hospital-acquired strains. Preventing the dissemination of these organisms throughout the general population requires a multifaceted approach, including screening and decolonisation, general hygiene and cleaning measures, antibiotic stewardship programmes and, in the future, vaccination. The current evidence on the prevention and control of CA-MRSA is appraised and summarised in this review. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Bacterial Etiology and Antibiotic Resistance Profile of Community-Acquired Urinary Tract Infections in a Cameroonian City.

PubMed

Nzalie, Rolf Nyah-Tuku; Gonsu, Hortense Kamga; Koulla-Shiro, Sinata

2016-01-01

Introduction. Community-acquired urinary tract infections (CAUTIs) are usually treated empirically. Geographical variations in etiologic agents and their antibiotic sensitivity patterns are common. Knowledge of antibiotic resistance trends is important for improving evidence-based recommendations for empirical treatment of UTIs. Our aim was to determine the major bacterial etiologies of CAUTIs and their antibiotic resistance patterns in a cosmopolitan area of Cameroon for comparison with prescription practices of local physicians. Methods. We performed a cross-sectional descriptive study at two main hospitals in Yaoundé, collecting a clean-catch mid-stream urine sample from 92 patients having a clinical diagnosis of UTI. The empirical antibiotherapy was noted, and identification of bacterial species was done on CLED agar; antibiotic susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Results. A total of 55 patients had samples positive for a UTI. Ciprofloxacin and amoxicillin/clavulanic acid were the most empirically prescribed antibiotics (30.9% and 23.6%, resp.); bacterial isolates showed high prevalence of resistance to both compounds. Escherichia coli (50.9%) was the most common pathogen, followed by Klebsiella pneumoniae (16.4%). Prevalence of resistance for ciprofloxacin was higher compared to newer quinolones. Conclusions. E. coli and K. pneumoniae were the predominant bacterial etiologies; the prevalence of resistance to commonly prescribed antibiotics was high.

[Clinical features and outcome of community-acquired methicillin-resistant Staphylococcus aureus pneumonia].

PubMed

Obed, Mora; García-Vidal, Carolina; Pessacq, Pedro; Mykietiuk, Analia; Viasus, Diego; Cazzola, Laura; Domínguez, M Angeles; Calmaggi, Anibal; Carratalà, Jordi

2014-01-01

The aim of this study is to describe the epidemiological and clinical features, treatment and prognosis of community-acquired pneumonia (CAP) caused by methicillin-resistant Staphylococcus aureus (MRSA) in two different geographic regions where community-acquired MRSA (CA-MRSA) infections have different frequencies. Observational study of patients admitted to two hospitals (one in Argentina, the other in Spain) between March 2008 and June 2012. We documented 16 cases of CAP caused by MRSA. MRSA accounted for 15 of 547 (2.7%) cases of CAP in Hospital Rodolfo Rossi and 1 of 1258 (0,08%) cases at the Hospital Universitari de Bellvitge (P ≤ .001). Most patients were young and previously healthy. Multilobar infiltrates, cavitation and skin and soft tissue involvement were frequent. All patients had positive blood cultures. Five patients required admission to the intensive care unit. Early mortality (≤ 48 hours) was 19%, and overall mortality (≤ 30 days) was 25%. CAP caused by MRSA causes high morbidity and mortality rates. It should be suspected in areas with a high prevalence of CA-MRSA infections, and especially in young and healthy patients who present with multilobar pneumonia with cavitation. Mortality is mainly related to septic shock and respiratory failure and occurs early in most cases. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies.

PubMed

Lim, Sun Min; Syn, Nicholas L; Cho, Byoung Chul; Soo, Ross A

2018-04-01

The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mitogen-activated Protein Kinase (MAPK) Hyperactivation and Enhanced NRAS Expression Drive Acquired Vemurafenib Resistance in V600E BRAF Melanoma Cells*

PubMed Central

Lidsky, Michael; Antoun, Gamil; Speicher, Paul; Adams, Bartley; Turley, Ryan; Augustine, Christi; Tyler, Douglas; Ali-Osman, Francis

2014-01-01

Although targeting the V600E activating mutation in the BRAF gene, the most common genetic abnormality in melanoma, has shown clinical efficacy in melanoma patients, response is, invariably, short lived. To better understand mechanisms underlying this acquisition of resistance to BRAF-targeted therapy in previously responsive melanomas, we induced vemurafenib resistance in two V600E BRAF+ve melanoma cell lines, A375 and DM443, by serial in vitro vemurafenib exposure. The resulting approximately 10-fold more vemurafenib-resistant cell lines, A375rVem and D443rVem, had higher growth rates and showed differential collateral resistance to cisplatin, melphalan, and temozolomide. The acquisition of vemurafenib resistance was associated with significantly increased NRAS levels in A375rVem and D443rVem, increased activation of the prosurvival protein, AKT, and the MAPKs, ERK, JNK, and P38, which correlated with decreased levels of the MAPK inhibitor protein, GSTP1. Despite the increased NRAS, whole exome sequencing showed no NRAS gene mutations. Inhibition of all three MAPKs and siRNA-mediated NRAS suppression both reversed vemurafenib resistance significantly in A375rVem and DM443rVem. Together, the results indicate a mechanism of acquired vemurafenib resistance in V600E BRAF+ve melanoma cells that involves increased activation of all three human MAPKs and the PI3K pathway, as well as increased NRAS expression, which, contrary to previous reports, was not associated with mutations in the NRAS gene. The data highlight the complexity of the acquired vemurafenib resistance phenotype and the challenge of optimizing BRAF-targeted therapy in this disease. They also suggest that targeting the MAPKs and/or NRAS may provide a strategy to mitigate such resistance in V600E BRAF+ve melanoma. PMID:25063807

Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells.

PubMed

Lidsky, Michael; Antoun, Gamil; Speicher, Paul; Adams, Bartley; Turley, Ryan; Augustine, Christi; Tyler, Douglas; Ali-Osman, Francis

2014-10-03

Although targeting the V600E activating mutation in the BRAF gene, the most common genetic abnormality in melanoma, has shown clinical efficacy in melanoma patients, response is, invariably, short lived. To better understand mechanisms underlying this acquisition of resistance to BRAF-targeted therapy in previously responsive melanomas, we induced vemurafenib resistance in two V600E BRAF+ve melanoma cell lines, A375 and DM443, by serial in vitro vemurafenib exposure. The resulting approximately 10-fold more vemurafenib-resistant cell lines, A375rVem and D443rVem, had higher growth rates and showed differential collateral resistance to cisplatin, melphalan, and temozolomide. The acquisition of vemurafenib resistance was associated with significantly increased NRAS levels in A375rVem and D443rVem, increased activation of the prosurvival protein, AKT, and the MAPKs, ERK, JNK, and P38, which correlated with decreased levels of the MAPK inhibitor protein, GSTP1. Despite the increased NRAS, whole exome sequencing showed no NRAS gene mutations. Inhibition of all three MAPKs and siRNA-mediated NRAS suppression both reversed vemurafenib resistance significantly in A375rVem and DM443rVem. Together, the results indicate a mechanism of acquired vemurafenib resistance in V600E BRAF+ve melanoma cells that involves increased activation of all three human MAPKs and the PI3K pathway, as well as increased NRAS expression, which, contrary to previous reports, was not associated with mutations in the NRAS gene. The data highlight the complexity of the acquired vemurafenib resistance phenotype and the challenge of optimizing BRAF-targeted therapy in this disease. They also suggest that targeting the MAPKs and/or NRAS may provide a strategy to mitigate such resistance in V600E BRAF+ve melanoma. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Loss of EGFR confers acquired resistance to AZD9291 in an EGFR-mutant non-small cell lung cancer cell line with an epithelial-mesenchymal transition phenotype.

PubMed

Xu, Jing; Zhao, Xiaoting; He, Dengfeng; Wang, Jinghui; Li, Weiying; Liu, Yinghui; Ma, Li; Jiang, Mei; Teng, Yu; Wang, Ziyu; Gu, Meng; Wu, Jianbin; Wang, Yue; Yue, Wentao; Zhang, Shucai

2018-05-24

AZD9291 is an irreversible, small-molecule inhibitor which has potency against mutant EGFR- and T790M-resistant mutation. Despite the encouraging efficacy in clinical, the acquired resistance will finally occur. Further study will need to be done to identify the acquired resistance mechanisms and determine the next treatment. We established an AZD9291-resistant cell line (HCC827/AZDR) from parental HCC827 cell line through stepwise pulsed selection of AZD9291. The expression of EGFR and its downstream pathways were determined by western blot analysis or immunofluorescence assay. The sensitivity to indicated agents were evaluated by MTS. Compared with parental HCC827 cells, the HCC827/AZDR cells showed high resistance to AZD9291 and other EGFR-TKIs, and exhibited a mesenchymal-like phenotype. Almost complete loss of EGFR expression was observed in HCC827/AZDR cells. But the activation of downstream pathway, MAPK signaling, was found in HCC827/AZDR cells even in the presence of AZD9291. Inhibition of MAPK signaling had no effect on cell viability of HCC827/AZDR and could not reverse AZD9291 resistance because of the subsequent activation of AKT signaling. When treated with the combination of AKT and MAPK inhibitor, HCC827/AZDR showed remarkable growth inhibition. Loss of EGFR could be proposed as a potential acquired resistance mechanism of AZD9291 in EGFR-mutant NSCLC cells with an EMT phenotype. Despite the loss of EGFR, the activation of MAPK pathway which had crosstalk with AKT pathway could maintain the proliferation and survival of resistant cells. Blocking MAPK and AKT signaling may be a potential therapeutic strategy following AZD9291 resistance.

Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

PubMed Central

2015-01-01

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties. PMID:25383627

Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

DOE PAGES

Hanan, Emily J.; Eigenbrot, Charles; Bryan, Marian C.; ...

2014-11-10

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. Here in this paper, wemore » describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.« less

Prognostic value of inflammation-based markers in patients with pancreatic cancer administered gemcitabine and erlotinib.

PubMed

Lee, Jae Min; Lee, Hong Sik; Hyun, Jong Jin; Choi, Hyuk Soon; Kim, Eun Sun; Keum, Bora; Seo, Yeon Seok; Jeen, Yoon Tae; Chun, Hoon Jai; Um, Soon Ho; Kim, Chang Duck

2016-07-15

To evaluate the value of systemic inflammation-based markers as prognostic factors for advanced pancreatic cancer (PC). Data from 82 patients who underwent combination chemotherapy with gemcitabine and erlotinib for PC from 2011 to 2014 were collected retrospectively. Data that included the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio, and the C-reactive protein (CRP)-to-albumin (CRP/Alb) ratio were analyzed. Kaplan-Meier curves, and univariate and multivariate Cox proportional hazards regression analyses were used to identify the prognostic factors associated with progression-free survival (PFS) and overall survival (OS). The univariate analysis demonstrated the prognostic value of the NLR (P = 0.049) and the CRP/Alb ratio (P = 0.047) in relation to PFS, and a positive relationship between an increase in inflammation-based markers and a poor prognosis in relation to OS. The multivariate analysis determined that an increased NLR (hazard ratio = 2.76, 95%CI: 1.33-5.75, P = 0.007) is an independent prognostic factor for poor OS. There was no association between the PLR and the patients' prognoses in those who had received chemotherapy that comprised gemcitabine and erlotinib in combination. The Kaplan-Meier method and the log-rank test determined significantly worse outcomes in relation to PFS and OS in patients with an NLR > 5 or a CRP/Alb ratio > 5. Systemic inflammation-based markers, including increases in the NLR and the CRP/Alb ratio, may be useful for predicting PC prognoses.

Community-acquired necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus ST30-SCCmecIVc-spat019-PVL positive in San Antonio de Areco, Argentina.

PubMed

Fernandez, Silvina; Murzicato, Sofía; Sandoval, Orlando; Fernández-Canigia, Liliana; Mollerach, Marta

2015-01-01

Community-acquired methicillin-resistant Staphylococcus aureus is the first cause of skin and soft tissue infections, but can also produce severe diseases such as bacteremia, osteomyelitis and necrotizing pneumonia. Some S. aureus lineages have been described in cases of necrotizing pneumonia worldwide, usually in young, previously healthy patients. In this work, we describe a fatal case of necrotizing pneumonia due to community-acquired methicillin-resistant S. aureus clone ST30-SCCmecIVc-spat019-PVL positive in an immunocompetent adult patient. Copyright © 2014 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Antibiotic Resistance-Susceptibility Profiles of Streptococcus thermophilus Isolated from Raw Milk and Genome Analysis of the Genetic Basis of Acquired Resistances

PubMed Central

Flórez, Ana B.; Mayo, Baltasar

2017-01-01

-10. Four strain-specific amino acid substitutions in the RsmG methyltransferase were scored in this strain; these might be associated to its streptomycin/neomycin resistance. Under yogurt manufacturing and storage conditions, no transfer of either tet(S) or ermB from S. thermophilus to L. delbrueckii was detected. The present results contribute toward characterisation of the antibiotic resistance profiles in S. thermophilus, provide evidence for the genetic basis of acquired resistances and deepen on their transference capability. PMID:29312272

Trade-offs with stability modulate innate and mutationally acquired drug-resistance in bacterial dihydrofolate reductase enzymes.

PubMed

Matange, Nishad; Bodkhe, Swapnil; Patel, Maitri; Shah, Pooja

2018-06-05

Structural stability is a major constraint on the evolution of protein sequences. However, under strong directional selection, mutations that confer novel phenotypes but compromise structural stability of proteins may be permissible. During the evolution of antibiotic resistance, mutations that confer drug resistance often have pleiotropic effects on the structure and function of antibiotic-target proteins, usually essential metabolic enzymes. In this study, we show that trimethoprim-resistant alleles of dihydrofolate reductase from Escherichia coli (EcDHFR) harbouring the Trp30Gly, Trp30Arg or Trp30Cys mutations are significantly less stable than the wild type making them prone to aggregation and proteolysis. This destabilization is associated with lower expression level resulting in a fitness cost and negative epistasis with other TMP-resistant mutations in EcDHFR. Using structure-based mutational analysis we show that perturbation of critical stabilizing hydrophobic interactions in wild type EcDHFR enzyme explains the phenotypes of Trp30 mutants. Surprisingly, though crucial for the stability of EcDHFR, significant sequence variation is found at this site among bacterial DHFRs. Mutational and computational analyses in EcDHFR as well as in DHFR enzymes from Staphylococcus aureus and Mycobacterium tuberculosis demonstrate that natural variation at this site and its interacting hydrophobic residues, modulates TMP-resistance in other bacterial DHFRs as well, and may explain the different susceptibilities of bacterial pathogens to trimethoprim. Our study demonstrates that trade-offs between structural stability and function can influence innate drug resistance as well as the potential for mutationally acquired drug resistance of an enzyme. ©2018 The Author(s).

[Pathogen distribution and bacterial resistance in children with severe community-acquired pneumonia].

PubMed

Lu, Yun-Yun; Luo, Rong; Fu, Zhou

2017-09-01

To investigate the distribution of pathogens and bacterial resistance in children with severe community-acquired pneumonia (CAP). A total of 522 children with severe CAP who were hospitalized in 2016 were enrolled as study subjects. According to their age, they were divided into infant group (402 infants aged 28 days to 1 year), young children group (73 children aged 1 to 3 years), preschool children group (35 children aged 3 to 6 years), and school-aged children group (12 children aged ≥6 years). According to the onset season, all children were divided into spring group (March to May, 120 children), summer group (June to August, 93 children), autumn group (September to November, 105 children), and winter group (December to February, 204 children). Sputum specimens from the deep airway were collected from all patients. The phoenix-100 automatic bacterial identification system was used for bacterial identification and drug sensitivity test. The direct immunofluorescence assay was used to detect seven common respiratory viruses. The quantitative real-time PCR was used to detect Mycoplasma pneumoniae (MP) and Chlamydia trachomatis (CT). Of all the 522 children with severe CAP, 419 (80.3%) were found to have pathogens, among whom 190 (45.3%) had mixed infection. A total of 681 strains of pathogens were identified, including 371 bacterial strains (54.5%), 259 viral strains (38.0%), 12 fungal strains (1.8%), 15 MP strains (2.2%), and 24 CT strains (3.5%). There were significant differences in the distribution of bacterial, viral, MP, and fungal infections between different age groups (P<0.05). There were significant differences in the incidence rate of viral infection between different season groups (P<0.05), with the highest incidence rate in winter. The drug-resistance rates of Streptococcus pneumoniae to erythromycin, tetracycline, and clindamycin reached above 85%, and the drug-resistance rates of Staphylococcus aureus to penicillin, erythromycin, and clindamycin

The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma.

PubMed

Zhuang, Hongqing; Wang, Jun; Zhao, Lujun; Yuan, Zhiyong; Wang, Ping

2013-11-15

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung adenocarcinoma, and a theoretical basis exists for utilising whole brain radiotherapy (WBRT) combined with erlotinib for the treatment for brain metastases in patients with lung adenocarcinoma. This therapeutic regimen has the potential to be a revolutionary treatment for which the most appropriate indication is lung adenocarcinoma. Currently, there is no difference in the treatment of brain metastasis, especially multiple brain metastases, in patients with lung adenocarcinoma of patients with other lung carcinomas. Furthermore, limited clinical trials that combine a TKI with WBRT to treat multiple lung adenocarcinoma metastases have been conducted, and many clinical questions remain unanswered. Lung adenocarcinoma has a high propensity to metastasize to the brain, and targeted therapy has been widely used; however, clinical trials are necessary to provide data to support the combination of erlotinib and WBRT. Copyright © 2013 UICC.

Simultaneous targeting of EGFR, HER2, and HER4 by afatinib overcomes intrinsic and acquired cetuximab resistance in head and neck squamous cell carcinoma cell lines.

PubMed

De Pauw, Ines; Lardon, Filip; Van den Bossche, Jolien; Baysal, Hasan; Fransen, Erik; Deschoolmeester, Vanessa; Pauwels, Patrick; Peeters, Marc; Vermorken, Jan Baptist; Wouters, An

2018-06-01

The epidermal growth factor receptor (EGFR, HER1) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). After initial promising results with EGFR-targeted therapies such as cetuximab, therapeutic resistance has become a major clinical problem, and new treatment options are therefore necessary. Moreover, the relationship between HER receptors, anti-EGFR therapies, and the human papillomavirus (HPV) status in HNSCC is not fully understood. In contrast to first-generation EGFR inhibitors, afatinib irreversibly inhibits multiple HER receptors simultaneously. Therefore, treatment with afatinib might result in a more pronounced therapeutic benefit, even in patients experiencing cetuximab resistance. In this study, the cytotoxic effect of afatinib as single agent and in combination with cisplatin was investigated in cetuximab-sensitive, intrinsically cetuximab-resistant, and acquired cetuximab-resistant HNSCC cell lines with different HPV status under normoxia and hypoxia. Furthermore, the influence of cetuximab resistance, HPV, and hypoxia on the expression of HER receptors was investigated. Our results demonstrated that afatinib was able to establish cytotoxicity in cetuximab-sensitive, intrinsically cetuximab-resistant, and acquired cetuximab-resistant HNSCC cell lines, independent of the HPV status. However, cross-resistance between cetuximab and afatinib might be possible. Treatment with afatinib caused a G 0 /G 1 cell cycle arrest as well as induction of apoptotic cell death. Additive to antagonistic interactions between afatinib and cisplatin could be observed. Neither cetuximab resistance nor HPV status significantly influenced the expression of HER receptors in HNSCC cell lines. In contrast, the expression of EGFR, HER2, and HER3 was significantly altered under hypoxia. Oxygen deficiency is a common characteristic of HNSCC tumors, and these hypoxic tumor regions often contain cells that are more resistant to treatment. However, we observed

Differences in microbiological profile between community-acquired, healthcare-associated and hospital-acquired infections.

PubMed

Cardoso, Teresa; Ribeiro, Orquídea; Aragão, Irene; Costa-Pereira, Altamiro; Sarmento, António

2013-01-01

Microbiological profiles were analysed and compared for intra-abdominal, urinary, respiratory and bloodstream infections according to place of acquisition: community-acquired, with a separate analysis of healthcare-associated, and hospital-acquired. Prospective cohort study performed at a university tertiary care hospital over 1 year. Inclusion criteria were meeting the Centers for Disease Control definition of intra-abdominal, urinary, respiratory and bloodstream infections. A total of 1035 patients were included in the study. More than 25% of intra-abdominal infections were polymicrobial; multi-drug resistant gram-negatives were 38% in community-acquired, 50% in healthcare-associated and 57% in hospital-acquired. E. coli was the most prevalent among urinary infections: 69% in community-acquired, 56% in healthcare-associated and 26% in hospital-acquired; ESBL producers' pathogens were 10% in healthcare-associated and 3% in community-acquired and hospital-acquired. In respiratory infections Streptococcus pneumoniae was the most prevalent in community-acquired (54%) and MRSA in healthcare-associated (24%) and hospital-acquired (24%). A significant association was found between MRSA respiratory infection and hospitalization in the previous year (adjusted OR = 6.3), previous instrumentation (adjusted OR = 4.3) and previous antibiotic therapy (adjusted OR = 5.7); no cases were documented among patients without risk factors. Hospital mortality rate was 10% in community-acquired, 14% in healthcare-associated and 19% in hospital-acquired infection. This study shows that healthcare-associated has a different microbiologic profile than those from community or hospital acquired for the four main focus of infection. Knowledge of this fact is important because the existing guidelines for community-acquired are not entirely applicable for this group of patients.

Utilising the EGFR interactome to identify mechanisms of drug resistance in non-small cell lung cancer - Proof of concept towards a systems pharmacology approach.

PubMed

Saafan, Hisham; Foerster, Sarah; Parra-Guillen, Zinnia P; Hammer, Elke; Michaelis, Martin; Cinatl, Jindrich; Völker, Uwe; Fröhlich, Holger; Kloft, Charlotte; Ritter, Christoph A

2016-10-30

Drug treatment of epidermal growth factor receptor (EGFR) positive non-small cell lung cancer has improved substantially by targeting activating mutations within the receptor tyrosine kinase domain. However, the development of drug resistance still limits this approach. As root causes, large heterogeneity between tumour entities but also within tumour cells have been suggested. Therefore, approaches to identify these multitude and complex mechanisms are urgently required. Affinity purification coupled with high resolution mass spectrometry was applied to isolate and characterise the EGFR interactome from HCC4006 non-small cell lung cancer cells and their variant HCC4006 r ERLO 0.5 adapted to grow in the presence of therapeutically relevant concentrations of erlotinib. Bioinformatics analyses were carried out to identify proteins and their related molecular functions that interact differentially with EGFR in the untreated state or when incubated with erlotinib prior to EGFR activation. Across all experimental conditions 375 proteins were detected to participate in the EGFR interactome, 90% of which constituted a complex protein interaction network that was bioinformatically reconstructed from literature data. Treatment of HCC4006 r ERLO 0.5 cells carrying a resistance phenotype to erlotinib was associated with an increase of protein levels of members of the clathrin-associated adaptor protein family AP2 (AP2A1, AP2A2, AP2B1), structural proteins of cytoskeleton rearrangement as well as signalling molecules such as Shc. Validation experiments confirmed activation of the Ras-Raf-Mek-Erk (MAPK)-pathway, of which Shc is an initiating adaptor molecule, in HCC4006 r ERLO 0.5 cells. Taken together, differential proteins in the EGFR interactome of HCC4006 r ERLO 0.5 cells were identified that could be related to multiple resistance mechanisms including alterations in growth factor receptor expression, cellular remodelling processes suggesting epithelial

Evolution of amoxicillin/clavulanate in the treatment of adults with acute bacterial rhinosinusitis and community-acquired pneumonia in response to antimicrobial-resistance patterns.

PubMed

File, Thomas M; Benninger, Michael S; Jacobs, Michael R

2004-06-01

Current treatment guidelines for community-acquired respiratory tract infections no longer depend solely on the characteristics of the patient and the clinical syndrome, but on those of the offending pathogen, including presence and level of antimicrobial resistance. The most common respiratory tract pathogens known to cause acute bacterial rhinosinusitis (ABRS) and community-acquired pneumonia (CAP) include Streptococcus pneumoniae and Haemophilus influenzae. The prevalence of antimicrobial resistance, especially b-lactum and macrolide resistance, among S pneumoniae and H influenzae has increased dramatically during the past 2 decades, diminishing the activity of many older antimicrobials against resistant organisms. A pharmacokinetically enhanced formulation of amoxicillin/clavulanate has been developed to fulfill the need for an oral b-lactam antimicrobial that achieves a greater time that the serum drug concentration exceeds the minimum inhibitory concentration (T > MIC) of antimicrobials against pathogens than conventional formulations to improve activity against S pneumoniae with reduced susceptibility to penicillin. The b-lactamase inhibitor clavulanate allows for coverage of b-lactamase-producing pathogens, such as H influenzae and M catarrhalis. This article reviews the rationale for, and evolution of, oral amoxicillin clavulanate for ABRS and CAP

Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer.

PubMed

Tanimoto, Azusa; Takeuchi, Shinji; Arai, Sachiko; Fukuda, Koji; Yamada, Tadaaki; Roca, Xavier; Ong, S Tiong; Yano, Seiji

2017-06-15

Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR . ©2016 American Association for Cancer Research.

The impact of nosocomially-acquired resistant Pseudomonas aeruginosa infection in a burn unit.

PubMed

Armour, Alexis D; Shankowsky, Heather A; Swanson, Todd; Lee, Jonathan; Tredget, Edward E

2007-07-01

Nosocomially-acquired Pseudomonas aeruginosa remains a serious cause of infection and septic mortality in burn patients. This study was conducted to quantify the impact of nosocomially-transmitted resistant P. aeruginosa in a burn population. Using a TRACS burn database, 48 patients with P. aeruginosa resistant to gentamicin were identified (Pseudomonas group). Thirty-nine were case-matched to controls without resistant P. aeruginosa cultures (control group) for age, total body surface area, admission year, and presence of inhalation injury. Mortality and various morbidity endpoints were examined, as well as antibiotic costs. There was a significantly higher mortality rate in the Pseudomonas group (33% vs. 8%, p < 0.001) compared with in the control group. Length of stay was increased in the Pseudomonas group (73.4 +/- 11.6 vs. 58.3 +/- 8.3 days). Ventilatory days (23.9 +/- 5.4 vs. 10.8 +/- 2.4, p < 0.05), number of surgical procedures (5.2 +/- 0.6 vs. 3.4 +/- 0.4, p < 0.05), and amount of blood products used (packed cells 51.1 +/- 8.0 vs. 21.1 +/- 3.4, p < 0.01; platelets 11.9 +/- 3.0 vs. 1.4 +/- 0.7, p < 0.01) were all significantly higher in the Pseudomonas group. Cost of antibiotics was also significantly higher ($2,658.52 +/- $647.93 vs. $829.22 +/- $152.82, p < 0.01). Nosocomial colonization or infection, or both, of burn patients with aminoglycoside-resistant P. aeruginosa is associated with significantly higher morbidity, mortality, and cost of care. Increased resource consumption did not prevent significantly higher mortality rates when compared with that of control patients. Thus, prevention, identification, and eradication of nosocomial Pseudomonas contamination are critical for cost-effective, successful burn care.

Expression of the human NAD(P)-metabolizing ectoenzyme CD38 compromises systemic acquired resistance in Arabidopsis.

PubMed

Zhang, Xudong; Mou, Zhonglin

2012-09-01

Plant systemic acquired resistance (SAR) is a long-lasting, broad-spectrum immune response that is mounted after primary pathogen infection. Although SAR has been extensively researched, the molecular mechanisms underlying its activation have not been completely understood. We have previously shown that the electron carrier NAD(P) leaks into the plant extracellular compartment upon pathogen attack and that exogenous NAD(P) activates defense gene expression and disease resistance in local treated leaves, suggesting that extracellular NAD(P) [eNAD(P)] might function as a signal molecule activating plant immune responses. To further establish the function of eNAD(P) in plant immunity, we tested the effect of exogenous NAD(P) on resistance gene-mediated hypersensitive response (HR) and SAR. We found that exogenous NAD(P) completely suppresses HR-mediated cell death but does not affect HR-mediated disease resistance. Local application of exogenous NAD(P) is unable to induce SAR in distal tissues, indicating that eNAD(P) is not a sufficient signal for SAR activation. Using transgenic Arabidopsis plants expressing the human NAD(P)-metabolizing ectoenzyme CD38, we demonstrated that altering eNAD(P) concentration or signaling compromises biological induction of SAR. This result suggests that eNAD(P) may play a critical signaling role in activation of SAR.

Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors.

PubMed

Taniguchi, Hirokazu; Takeuchi, Shinji; Fukuda, Koji; Nakagawa, Takayuki; Arai, Sachiko; Nanjo, Shigeki; Yamada, Tadaaki; Yamaguchi, Hiroyuki; Mukae, Hiroshi; Yano, Seiji

2017-01-01

Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Interpretation of deep directional resistivity measurements acquired in high-angle and horizontal wells using 3-D inversion

NASA Astrophysics Data System (ADS)

Puzyrev, Vladimir; Torres-Verdín, Carlos; Calo, Victor

2018-05-01

The interpretation of resistivity measurements acquired in high-angle and horizontal wells is a critical technical problem in formation evaluation. We develop an efficient parallel 3-D inversion method to estimate the spatial distribution of electrical resistivity in the neighbourhood of a well from deep directional electromagnetic induction measurements. The methodology places no restriction on the spatial distribution of the electrical resistivity around arbitrary well trajectories. The fast forward modelling of triaxial induction measurements performed with multiple transmitter-receiver configurations employs a parallel direct solver. The inversion uses a pre-conditioned gradient-based method whose accuracy is improved using the Wolfe conditions to estimate optimal step lengths at each iteration. The large transmitter-receiver offsets, used in the latest generation of commercial directional resistivity tools, improve the depth of investigation to over 30 m from the wellbore. Several challenging synthetic examples confirm the feasibility of the full 3-D inversion-based interpretations for these distances, hence enabling the integration of resistivity measurements with seismic amplitude data to improve the forecast of the petrophysical and fluid properties. Employing parallel direct solvers for the triaxial induction problems allows for large reductions in computational effort, thereby opening the possibility to invert multiposition 3-D data in practical CPU times.

Erlotinib and radiation therapy for elderly patients with esophageal cancer - clinical and correlative results from a prospective multicenter phase 2 trial.

PubMed

Iyer, Renuka; Chhatrala, Ravi; Shefter, Tracey; Yang, Gary; Malhotra, Usha; Tan, Wei; Levea, Charles; Robins, Melissa; Khushalani, Nikhil

2013-01-01

Elderly patients with esophageal cancer who are not candidates for chemoradiation may benefit from targeted agents; hence erlotinib combined with radiotherapy was evaluated in this trial. Patients >65 years with carcinoma of the thoracic esophagus or gastroesophageal junction who were not eligible for platinum-based treatment received erlotinib daily for 1 year starting on day 1 of radiotherapy [50.4 Gy days 1-28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary endpoint was overall survival (OS), and secondary endpoints were complete response, progression-free survival (PFS) and toxicity. The ECOG performance status in the 17 study patients was 0,1 and 2 in 2, 12 and 3 patients, respectively; 1, 5, 7 and 4 patients were in stage I, II, III and IV, respectively; adenocarcinoma was noted in 16 patients and squamous cell carcinoma in 1; there were 3 current, 12 past and 2 never smokers. Median OS was 7.3 months (95% confidence interval, CI: 3.8-22.3) with 14 deaths. There were 2 mucosal complete responses, 1 residual carcinoma in situ and 3 partial endoscopic responses in 9 patients who had endoscopy after radiotherapy. Estimated PFS was 4.5 months (95% CI: 2.4-7.3). Progression was distant (n = 3), locoregional (n = 6), unknown (n = 5) and too early (n = 3). Estimated 1-year survival was 29% (95% CI: 11-51%), 5 patients lived >12 months. Treatment-related toxicities of grade 3-4 occurred in 5 patients. Patients with epidermal growth factor receptor amplification and never smokers had the longest OS (22.3 and 16.6 months, respectively). Erlotinib with radiotherapy is tolerable and warrants further biomarker-driven evaluation in this population. Copyright © 2013 S. Karger AG, Basel.

Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

DTIC Science & Technology

2015-08-01

AWARD NUMBER: W81XWH-13-1-0226 TITLE: Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in...REPORT TYPE Annual 3. DATES COVERED 1 Aug 2014 - 31 Jul 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Deficient BIM Expression as a Mechanism of...the time of resistance. We are now using these patient-derived cell lines to assess BIM levels and apoptotic response to next-generation inhibitors

Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

DTIC Science & Technology

2015-08-01

AWARD NUMBER: W81XWH-13-1-0227 TITLE: Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in...TYPE Annual 3. DATES COVERED 1 Aug 2014 - 31 Jul 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Deficient BIM Expression as a Mechanism of Intrinsic...time of resistance. We are now using these patient-derived cell lines to assess BIM levels and apoptotic response to next-generation inhibitors. The

Overexpression of ATP-Binding Cassette Transporter ABCG2 as a Potential Mechanism of Acquired Resistance to Vemurafenib in BRAF(V600E) Mutant Cancer Cells

PubMed Central

Wu, Chung-Pu; Sim, Hong-May; Huang, Yang-Hui; Liu, Yen-Chen; Hsiao, Sung-Han; Cheng, Hsing-Wen; Li, Yan-Qing; Ambudkar, Suresh V.; Hsu, Sheng-Chieh

2012-01-01

Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation. PMID:23153455

Mechanism of c-Met and EGFR tyrosine kinase inhibitor resistance through epithelial mesenchymal transition in non-small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rastogi, Ichwaku; Rajanna, Supriya; Webb, Andrew

According to currently available estimates from Cancer Research UK, 14.1 million new lung cancer cases were diagnosed and a staggering 8.2 million people worldwide died from lung cancer in 2012. EGFR and c-Met are two tyrosine kinase receptors most commonly overexpressed or mutated in Non-small Cell Lung Cancer (NSCLC) resulting in increased proliferation and survival of lung cancer cells. Tyrosine kinase inhibitors (TKIs), such as erlotinib, approved by the FDA as first/second line therapy for NSCLC patients have limited clinical efficacy due to acquired resistance. In this manuscript, we investigate and discuss the role of epithelial mesenchymal transition (EMT) inmore » the development of resistance against EGFR and c-Met TKIs in NSCLC. Our findings show that Zeb-1, a transcriptional repressor of E-Cadherin, is upregulated in TKI-resistant cells causing EMT. We observed that TKI-resistant cells have increased gene and protein expression of EMT related proteins such as Vimentin, N-Cadherin, β-Catenin and Zeb-1, while expression of E-Cadherin, an important cell adhesion molecule, was suppressed. We also confirmed that TKI-resistant cells display mesenchymal cell type morphology, and have upregulation of β-Catenin which may regulate expression of Zeb-1, a transcriptional repressor of E-Cadherin in TKI-resistant NSCLC cells. Finally, we show that down-regulating Zeb-1 by inducing miR-200a or β-Catenin siRNA can increase drug sensitivity of TKI-resistant cells. - Highlights: • Resistance to TKIs in NSCLC cells is mediated via modulation in EMT related proteins. • EMT may induce c-Met mediated TKI resistance, similar to EGFR TKI resistance. • Role of β-catenin and cadherins in TKI resistance was validated by FACS and qPCR. • Knockdown of β-catenin or Zeb-1 can increase TKI sensitivity in TKI-resistant cells. • Targeting key EMT related proteins may overcome TKI resistance in NSCLC.« less

Acquired resistance to tyrosine kinase inhibitors may be linked with the decreased sensitivity to X-ray irradiation

PubMed Central

Sorokin, Maxim; Kholodenko, Roman; Grekhova, Anna; Suntsova, Maria; Pustovalova, Margarita; Vorobyeva, Natalia; Kholodenko, Irina; Malakhova, Galina; Garazha, Andrew; Nedoluzhko, Artem; Vasilov, Raif; Poddubskaya, Elena; Kovalchuk, Olga; Adamyan, Leila; Prassolov, Vladimir; Allina, Daria; Kuzmin, Denis; Ignatev, Kirill; Osipov, Andreyan; Buzdin, Anton

2018-01-01

Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC50) increased by 25 – 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs. PMID:29435166

Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial.

PubMed

Markóczy, Zsolt; Sárosi, Veronika; Kudaba, Iveta; Gálffy, Gabriella; Turay, Ülkü Yilmaz; Demirkazik, Ahmet; Purkalne, Gunta; Somfay, Attila; Pápai-Székely, Zsolt; Rásó, Erzsébet; Ostoros, Gyula

2018-05-25

Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection. 651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS). 62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9-15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation. Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure. ClinicalTrials.gov Identifier: NCT01609543.

Optimal strength and timing of steroids in the management of erlotinib-related skin toxicities in a post-marketing surveillance study (POLARSTAR) of 9909 non-small-cell lung cancer patients.

PubMed

Yamazaki, Naoya; Kiyohara, Yoshio; Kudoh, Shoji; Seki, Akihiro; Fukuoka, Masahiro

2016-04-01

Skin toxicities, such as rash, are the most common adverse reactions associated with erlotinib. Steroids are a key treatment option for rash management; however, optimal timing of administration and selection of steroid strength have not been fully established. In this surveillance study of Japanese non-small-cell lung cancer (NSCLC) patients treated with erlotinib, rash management using topical steroids was analyzed in routine clinical practice. From December 2007 to October 2009, all recurrent/advanced NSCLC patients in Japan treated with erlotinib were enrolled into this study (POst-Launch All-patient Registration Surveillance in TARceva). The observation period was 12 months, and data for all adverse events were collected. Erlotinib-related rash, interventions for the symptoms, and outcomes of the interventions were analyzed. A total of 9909 patients were evaluated. Rash occurred in 67.4 % of patients; grade 1, 2, and 3 rash were observed in 26.8 %, 32.4 %, and 7.2 % of patients, respectively. The most common management strategy was topical steroids in 75.0 % of patients with rash. Regardless of rash grade, earlier initiation of steroids resulted in quicker recovery. In those for whom topical steroids were initiated more than 21 days after rash onset, median recovery time was more than 100 days regardless of rash grade, compared with those treated before rash onset, whose median time to recovery was 35-51 days, depending on rash grade. Median time to recovery of rash in the group initiated on medium-rank steroids then changed to strong-rank steroids was 47, 98, and 103 days for those with grade 1, 2, and 3 rash, respectively, compared with 39, 53, and 73 days median recovery for grade 1, 2, and 3 rash, respectively, in patients initiated on strong-rank steroids. Earlier initiation of topical steroids for the management of rash with strong or higher-rank steroids could achieve faster improvement.

Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen in orthopaedics.

PubMed

Marcotte, Anthony L; Trzeciak, Marc A

2008-02-01

Staphylococcus aureus (S aureus) remains one of the most common pathogens for skin and soft-tissue infections encountered by the orthopaedic surgeon. Community-acquired methicillin-resistant S aureus (CA-MRSA) has become increasingly prevalent, particularly among athletes, children in day care, homeless persons, intravenous drug users, men who have sex with men, military recruits, certain minorities (ie, Alaskan Natives, Native Americans, Pacific Islanders), and prison inmates. Risk factors include antibiotic use within the preceding year, crowded living conditions, compromised skin integrity, contaminated surfaces, frequent skin-to-skin contact, shared items, and suboptimal cleanliness. When a patient presents with a skin or soft-tissue infection, the clinician should determine whether an abscess or other infection needs to be surgically incised and drained. Cultures should be performed. When the patient is a member of an at-risk group or has any of the risk factors for CA-MRSA, beta-lactam antibiotics (eg, methicillin) are no longer a reasonable choice for treatment. Empiric treatment should consist of non-beta-lactam antibiotics active against CA-MRSA.

Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus.

PubMed

Male, C; Mitchell, L; Julian, J; Vegh, P; Joshua, P; Adams, M; David, M; Andrew, M E

2001-02-15

Acquired activated protein C resistance (APCR) has been hypothesized as a possible mechanism by which antiphospholipid antibodies (APLAs) cause thrombotic events (TEs). However, available evidence for an association of acquired APCR with APLAs is limited. More importantly, an association of acquired APCR with TEs has not been demonstrated. The objective of the study was to determine, in pediatric patients with systemic lupus erythematosus (SLE), whether (1) acquired APCR is associated with the presence of APLAs, (2) APCR is associated with TEs, and (3) there is an interaction between APCR and APLAs in association with TEs. A cross-sectional cohort study of 59 consecutive, nonselected children with SLE was conducted. Primary clinical outcomes were symptomatic TEs, confirmed by objective radiographic tests. Laboratory testing included lupus anticoagulants (LAs), anticardiolipin antibodies (ACLAs), APC ratio, protein S, protein C, and factor V Leiden. The results revealed that TEs occurred in 10 (17%) of 59 patients. Acquired APCR was present in 18 (31%) of 58 patients. Acquired APCR was significantly associated with the presence of LAs but not ACLAs. Acquired APCR was also significantly associated with TEs. There was significant interaction between APCR and LAs in the association with TEs. Presence of both APCR and LAs was associated with the highest risk of a TE. Protein S and protein C concentrations were not associated with the presence of APLAs, APCR, or TEs. Presence of acquired APCR is a marker identifying LA-positive patients at high risk of TEs. Acquired APCR may reflect interference of LAs with the protein C pathway that may represent a mechanism of LA-associated TEs. (Blood. 2001;97:844-849)

Doxycycline for prevention of erlotinib-induced rash in patients with non-small-cell lung cancer (NSCLC) after failure of first-line chemotherapy: A randomized, open-label trial.

PubMed

Deplanque, Gaël; Gervais, Radj; Vergnenegre, Alain; Falchero, Lionel; Souquet, Pierre-Jean; Chavaillon, Jean-Michel; Taviot, Bruno; Fraboulet, Ghislaine; Saal, Hakim; Robert, Caroline; Chosidow, Olivier

2016-06-01

Rash is a common epidermal growth factor receptor inhibitor-induced toxicity that can impair quality of life and treatment compliance. We sought to evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer. This open-label, randomized, prospective, phase II trial was conducted in 147 patients with locally advanced or metastatic non-small-cell lung cancer progressing after first-line chemotherapy, randomized for 4 months with erlotinib alone 150 mg/d per os (control arm) or combined with doxycycline 100 mg/d (doxycycline arm). Incidence and severity of rash, compliance, survival, and safety were assessed. Baseline characteristics of the 147 patients were well balanced in the intent-to-treat population. Folliculitis occurred in 71% of patients in the doxycycline arm and 81% in the control arm (P = .175). The severity of folliculitis and other skin lesions was lower in the doxycycline arm compared with the control arm. Other adverse events were reported at a similar frequency across arms. There was no significant difference in survival between treatment arms. The open-label design of the study and the duration of the treatment with doxycycline are limitations. Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

High Prevalence of Multidrug-Resistant Community-Acquired Methicillin-Resistant Staphylococcus aureus at the Largest Veterinary Teaching Hospital in Costa Rica.

PubMed

Rojas, Irene; Barquero-Calvo, Elías; van Balen, Joany C; Rojas, Norman; Muñoz-Vargas, Lohendy; Hoet, Armando E

2017-09-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen associated with severe infections in companion animals present in the community, and it is diagnosed in animals admitted to veterinary hospitals. However, reports that describe the circulation of MRSA in animal populations and veterinary settings in Latin America are scarce. Therefore, the objective of this study was to determine the prevalence and investigate the molecular epidemiology of MRSA in the environment of the largest veterinary teaching hospital in Costa Rica. Preselected contact surfaces were sampled twice within a 6-week period. Antimicrobial resistance, SCCmec type, Panton-Valentine leukocidin screening, USA type, and clonality were assessed in all recovered isolates. Overall, MRSA was isolated from 26.5% (27/102) of the surfaces sampled, with doors, desks, and examination tables most frequently contaminated. Molecular analysis demonstrated a variety of surfaces from different sections of the hospital contaminated by three highly related clones/pulsotypes. All, but one of the isolates were characterized as multidrug-resistant SCCmec type IV-USA700, a strain sporadically described in other countries and often classified as community acquired. The detection and frequency of this unique strain in this veterinary setting suggest Costa Rica has a distinctive MRSA ecology when compared with other countries/regions. The high level of environmental contamination highlights the necessity to establish and enforce standard cleaning and disinfection protocols to minimize further spread of this pathogen and reduce the risk of nosocomial and/or occupational transmission of MRSA.

High Prevalence of Multidrug-Resistant Community-Acquired Methicillin-Resistant Staphylococcus aureus at the Largest Veterinary Teaching Hospital in Costa Rica

PubMed Central

Rojas, Irene; Barquero-Calvo, Elías; van Balen, Joany C.; Rojas, Norman; Muñoz-Vargas, Lohendy

2017-01-01

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen associated with severe infections in companion animals present in the community, and it is diagnosed in animals admitted to veterinary hospitals. However, reports that describe the circulation of MRSA in animal populations and veterinary settings in Latin America are scarce. Therefore, the objective of this study was to determine the prevalence and investigate the molecular epidemiology of MRSA in the environment of the largest veterinary teaching hospital in Costa Rica. Preselected contact surfaces were sampled twice within a 6-week period. Antimicrobial resistance, SCCmec type, Panton-Valentine leukocidin screening, USA type, and clonality were assessed in all recovered isolates. Overall, MRSA was isolated from 26.5% (27/102) of the surfaces sampled, with doors, desks, and examination tables most frequently contaminated. Molecular analysis demonstrated a variety of surfaces from different sections of the hospital contaminated by three highly related clones/pulsotypes. All, but one of the isolates were characterized as multidrug-resistant SCCmec type IV-USA700, a strain sporadically described in other countries and often classified as community acquired. The detection and frequency of this unique strain in this veterinary setting suggest Costa Rica has a distinctive MRSA ecology when compared with other countries/regions. The high level of environmental contamination highlights the necessity to establish and enforce standard cleaning and disinfection protocols to minimize further spread of this pathogen and reduce the risk of nosocomial and/or occupational transmission of MRSA. PMID:28816638

Metastasized lung cancer suppression by Morinda citrifolia (Noni) leaf compared to Erlotinib via anti-inflammatory, endogenous antioxidant responses and apoptotic gene activation.

PubMed

Lim, Swee-Ling; Mustapha, Noordin M; Goh, Yong-Meng; Bakar, Nurul Ain Abu; Mohamed, Suhaila

2016-05-01

Metastasized lung and liver cancers cause over 2 million deaths annually, and are amongst the top killer cancers worldwide. Morinda citrifolia (Noni) leaves are traditionally consumed as vegetables in the tropics. The macro and micro effects of M. citrifolia (Noni) leaves on metastasized lung cancer development in vitro and in vivo were compared with the FDA-approved anti-cancer drug Erlotinib. The extract inhibited the proliferation and induced apoptosis in A549 cells (IC50 = 23.47 μg/mL) and mouse Lewis (LL2) lung carcinoma cells (IC50 = 5.50 μg/mL) in vitro, arrested cancer cell cycle at G0/G1 phases and significantly increased caspase-3/-8 without changing caspase-9 levels. The extract showed no toxicity on normal MRC5 lung cells. Non-small-cell lung cancer (NSCLC) A549-induced BALB/c mice were fed with 150 and 300 mg/kg M. citrifolia leaf extract and compared with Erlotinib (50 mg/kg body weight) for 21 days. It significantly increased the pro-apoptotic TRP53 genes, downregulated the pro-tumourigenesis genes (BIRC5, JAK2/STAT3/STAT5A) in the mice tumours, significantly increased the anti-inflammatory IL4, IL10 and NR3C1 expression in the metastasized lung and hepatic cancer tissues and enhanced the NFE2L2-dependent antioxidant responses against oxidative injuries. The extract elevated serum neutrophils and reduced the red blood cells, haemoglobin, corpuscular volume and cell haemoglobin concentration in the lung cancer-induced mammal. It suppressed inflammation and oedema, and upregulated the endogenous antioxidant responses and apoptotic genes to suppress the cancer. The 300 mg/kg extract was more effective than the 50 mg/kg Erlotinib for most of the parameters measured.

Pertuzumab and Erlotinib in Patients With Relapsed Non-Small Cell Lung Cancer: A Phase II Study Using 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging

PubMed Central

Mileshkin, Linda; Townley, Peter; Gitlitz, Barbara; Eaton, Keith; Mitchell, Paul; Hicks, Rodney; Wood, Katie; Amler, Lucas; Fine, Bernard M.; Loecke, David; Pirzkall, Andrea

2014-01-01

Background. Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC). Methods. Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors. Results. Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%. Conclusion. FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles. PMID:24457379

Change in genotype of methicillin-resistant Staphylococcus aureus (MRSA) affects the antibiogram of hospital-acquired MRSA.

PubMed

Harada, Dai; Nakaminami, Hidemasa; Miyajima, Eri; Sugiyama, Taku; Sasai, Nao; Kitamura, Yoshinobu; Tamura, Taku; Kawakubo, Takashi; Noguchi, Norihisa

2018-07-01

Recently, the dissemination of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) into hospitals has frequently been reported worldwide. Hospital-acquired MRSA (HA-MRSA) strains exhibit high-level resistance to multiple antimicrobial agents, whereas CA-MRSA strains are usually susceptible to non-β-lactams. Thus, it is predicted that the antibiogram of the HA-MRSA population would change along with the change in genotype of MRSA. Here, we investigated the changes in the MRSA population along with the MRSA antibiogram in a hospital between 2010 and 2016. Staphylococcal cassette chromosome (SCC) mec typing showed that the predominant HA-MRSA strains in the hospital dramatically changed from SCCmec type II, which is the major type of HA-MRSA, to SCCmec type IV, which is the major type of CA-MRSA. Multilocus sequence typing revealed that the predominant SCCmec type IV strain was a clonal complex (CC) 8 clone, which is mainly found among CA-MRSA. Furthermore, the CC1-SCCmec type IV (CC1-IV) clone significantly increased. Both the CC8-IV and CC1-IV clones exhibited high antimicrobial susceptibility. The antibiogram change of the HA-MRSA population was consistent with the antimicrobial susceptibilities and increased prevalence of the CC8-IV and CC1-IV clones. Our data reveal that the change in the genotypes of MRSA strains could impact the antibiogram of HA-MRSA population. Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Community-acquired Staphylococcus aureus bacteremia in children: a cohort study for 2010-2014.

PubMed

Pérez, Guadalupe; Martiren, Soledad; Reijtman, Vanesa; Romero, Romina; Mastroianni, Alejandra; Casimir, Lidia; Bologna, Rosa

2016-12-01

Community-acquired methicillin-resistant Staphylococcus aureus infections are a common, serious problem in pediatrics. To describe antibiotic resistance in community-acquired Staphylococcus aureus (SA) bacteremias. To compare the characteristics of SA bacteremias in terms of methicillin resistance. Prospective cohort enrolled between January 2010 and December 2014. Inclusion criteria: infants and children between 30 days old and 16 years old hospitalized at the Hospital de Pediatria J. P. Garrahan due to community-acquired infections with SA growth identification in blood cultures. Exclusion criteria: having a history of recent hospitalization, attending a health care facility, living in a closed community, or having a venous catheter. Microbiological, demographic, and clinical characteristics were compared in terms of methicillin susceptibility. Statistical analysis: Stata10. A total of 208 children were included; boys: 141 (68%). Their median age was 60 months old (interquartile range: 29-130). Thirty-four patients (16%) had an underlying disease. Methicillin-resistant Staphylococcus aureus was identified in 136 children (65%). The rate of resistance to clindamycin was 9%. Significant statistical differences were observed in the rate of underlying disease, persistent bacteremia, sepsis at the time of admission, secondary source of infection, admission to the intensive care unit, and surgery requirement. Twelve patients (6%) died; community-acquired methicillin-resistant Staphylococcus aureus was identified in all of them. In the studied cohort, methicillin-resistant S taphylococcus aureus was predominant. The rate of resistance to clindamycin was 9%. Community-acquired methicillin-resistant Staphylococcus aureus infections prevailed among healthy children. Among patients with methicillin-resistant Staphylococcus aureus infections there was a higher rate of persistent bacteremia, admission to the ICU and surgery. Sociedad Argentina de Pediatría

Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies.

PubMed

Chen, Albert C; Migliaccio, Ilenia; Rimawi, Mothaffar; Lopez-Tarruella, Sara; Creighton, Chad J; Massarweh, Suleiman; Huang, Catherine; Wang, Yen-Chao; Batra, Surinder K; Gutierrez, M Carolina; Osborne, C Kent; Schiff, Rachel

2012-07-01

We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam + LT) or estrogen deprivation (ED + LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.

Upregulation of Mucin4 in ER-positive/HER2-Overexpressing Breast Cancer Xenografts with Acquired Resistance to Endocrine and HER2-Targeted Therapies

PubMed Central

Chen, Albert C.; Migliaccio, Ilenia; Rimawi, Mothaffar; Lopez-Tarruella, Sara; Creighton, Chad J.; Massarweh, Suleiman; Huang, Catherine; Wang, Yen-Chao; Batra, Surinder K.; Gutierrez, M. Carolina; Osborne, C. Kent; Schiff, Rachel

2012-01-01

Background We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. Methods MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin & eosin and mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER and HER2 signaling pathways was measured by immunohistochemistry and Western blotting. Results The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam+LT) or estrogen deprivation (ED+LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype—a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene, progesterone receptor. Conclusions Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive. PMID:22644656

Response to erlotinib in a patient with lung adenocarcinoma harbouring the EML4-ALK translocation: A case report.

PubMed

Alì, Greta; Chella, Antonio; Lupi, Cristiana; Proietti, Agnese; Niccoli, Cristina; Boldrini, Laura; Davini, Federico; Mussi, Alfredo; Fontanini, Gabriella

2015-04-01

Lung cancer is the leading cause of cancer-associated mortality worldwide, and the mainstay of treatment remains to be personalised therapy. Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have been reported to exert a significant impact in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harbouring mutations in the EGFR gene. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase ( EML4-ALK ) gene translocation has been described in a subset of patients with NSCLC and possesses potent oncogenic activity. This translocation represents one of the most novel molecular targets in the treatment of NSCLC. Patients who harbour the EML4-ALK rearrangement possess lung tumours that lack EGFR or K-ras mutations. The present study reports the case of a patient possessing the EML4-ALK rearrangement that was initially treated with erlotinib and achieved a lasting clinical response. To the best of our knowledge, the current study is the first report of a clinical response to EGFR-TKI in a patient with lung adenocarcinoma harbouring the EML4-ALK fusion gene, but no EGFR mutations. However, as the disease progressed, the ALK gene status of the tumour was investigated, and based upon a positive result, the patient was treated with crizotinib and achieved a complete response. In conclusion, the present study suggests that the EML4-ALK rearrangement is not always associated with resistance to EGFR-TKIs. Further studies are required to clarify the biological features of these tumours and to investigate the mechanisms underlying the primary resistance to EGFR-TKIs when the EML4-ALK rearrangement is present.

Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

PubMed Central

Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter

2015-01-01

Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received <3 effective drugs than among patients who received >3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954

Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma

PubMed Central

Goyal, Lipika; Saha, Supriya K.; Liu, Leah Y.; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G.; Lennerz, Jochen K.; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura; Sun, Jiaoyuan Elisabeth; Van Seventer, Emily E.; Gurski, Joseph M.; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P.; Stone, James R.; Iafrate, A. John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B.; Bardeesy, Nabeel; Zhu, Andrew X.

2017-01-01

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide development of future therapeutic strategies. PMID:28034880

Epidemiology, clinical manifestations, and treatment options for skin and soft tissue infection caused by community-acquired methicillin-resistant Staphylococcus aureus.

PubMed

Farley, Jason E

2008-02-01

This article reviews the evolving epidemiology of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and the appropriate outpatient management of CA-MRSA skin and soft tissue infection. Further, the paper will provide the basis upon which an individualized patient educational plan may be developed. To complete this review, a search of English language publications was conducted through Medline and CINAHL databases (1966-2006). The epidemiology of CA-MRSA is becoming increasingly complex. Research that addresses the impact of this organism in high-risk populations and within families is urgently needed. Nurse practitioners must remain informed of the epidemiology of common and emerging drug-resistant organisms in their patient populations.

Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI-Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation.

PubMed

Yamaoka, Toshimitsu; Ohmori, Tohru; Ohba, Motoi; Arata, Satoru; Kishino, Yasunari; Murata, Yasunori; Kusumoto, Sojiro; Ishida, Hiroo; Shirai, Takao; Hirose, Takashi; Ohnishi, Tsukasa; Sasaki, Yasutsuna

2016-12-01

Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μmol/L gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, PC-9DR4, and PC-9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with HSP90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment. Mol Cancer Ther; 15(12); 3040-54. ©2016 AACR. ©2016 American Association for Cancer Research.

Origin and evolution of European community-acquired methicillin-resistant Staphylococcus aureus.

PubMed

Stegger, Marc; Wirth, Thierry; Andersen, Paal S; Skov, Robert L; De Grassi, Anna; Simões, Patricia Martins; Tristan, Anne; Petersen, Andreas; Aziz, Maliha; Kiil, Kristoffer; Cirković, Ivana; Udo, Edet E; del Campo, Rosa; Vuopio-Varkila, Jaana; Ahmad, Norazah; Tokajian, Sima; Peters, Georg; Schaumburg, Frieder; Olsson-Liljequist, Barbro; Givskov, Michael; Driebe, Elizabeth E; Vigh, Henrik E; Shittu, Adebayo; Ramdani-Bougessa, Nadjia; Rasigade, Jean-Philippe; Price, Lance B; Vandenesch, Francois; Larsen, Anders R; Laurent, Frederic

2014-08-26

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations. With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib.

PubMed

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.

Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation.

PubMed

Shi, Puyu; Oh, You-Take; Deng, Liang; Zhang, Guojing; Qian, Guoqing; Zhang, Shuo; Ren, Hui; Wu, Grant; Legendre, Benjamin; Anderson, Emily; Ramalingam, Suresh S; Owonikoko, Taofeek K; Chen, Mingwei; Sun, Shi-Yong

2017-11-01

Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study. Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA. Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567-79. ©2017 AACR . ©2017 American Association for Cancer Research.

Optimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer Modeling

PubMed Central

Chmielecki, Juliann; Foo, Jasmine; Oxnard, Geoffrey R.; Hutchinson, Katherine; Ohashi, Kadoaki; Somwar, Romel; Wang, Lu; Amato, Katherine R.; Arcila, Maria; Sos, Martin L.; Socci, Nicholas D.; Viale, Agnes; de Stanchina, Elisa; Ginsberg, Michelle S.; Thomas, Roman K.; Kris, Mark G.; Inoue, Akira; Ladanyi, Marc; Miller, Vincent A.; Michor, Franziska; Pao, William

2012-01-01

Non–small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance. PMID:21734175

The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia.

PubMed

Ko, Tun Kiat; Chin, Hui San; Chuah, Charles T H; Huang, John W J; Ng, King-Pan; Khaw, Seong Lin; Huang, David C S; Ong, S Tiong

2016-01-19

Both germline polymorphisms and tumor-specific genetic alterations can determine the response of a cancer to a given therapy. We previously reported a germline deletion polymorphism in the BIM gene that was sufficient to mediate intrinsic resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), as well as other cancers [1]. The deletion polymorphism favored the generation of BIM splice forms lacking the pro-apoptotic BH3 domain, conferring a relative resistance to the TKI imatinib (IM). However, CML patients with the BIM deletion polymorphism developed both partial and complete IM resistance. To understand the mechanisms underlying the latter, we grew CML cells either with or without the BIM deletion polymorphism in increasing IM concentrations. Under these conditions, the BIM deletion polymorphism enhanced the emergence of populations with complete IM resistance, mimicking the situation in patients. Importantly, the combined use of TKIs with the BH3 mimetic ABT-737 overcame the BCR-ABL1-dependent and -independent resistance mechanisms found in these cells. Our results illustrate the interplay between germline and acquired genetic factors in confering TKI resistance, and suggest a therapeutic strategy for patients with complete TKI resistance associated with the BIM deletion polymorphism.

Systemic acquired resistance in moss: further evidence for conserved defense mechanisms in plants.

PubMed

Winter, Peter S; Bowman, Collin E; Villani, Philip J; Dolan, Thomas E; Hauck, Nathanael R

2014-01-01

Vascular plants possess multiple mechanisms for defending themselves against pathogens. One well-characterized defense mechanism is systemic acquired resistance (SAR). In SAR, a plant detects the presence of a pathogen and transmits a signal throughout the plant, inducing changes in the expression of various pathogenesis-related (PR) genes. Once SAR is established, the plant is capable of mounting rapid responses to subsequent pathogen attacks. SAR has been characterized in numerous angiosperm and gymnosperm species; however, despite several pieces of evidence suggesting SAR may also exist in non-vascular plants6-8, its presence in non-vascular plants has not been conclusively demonstrated, in part due to the lack of an appropriate culture system. Here, we describe and use a novel culture system to demonstrate that the moss species Amblystegium serpens does initiate a SAR-like reaction upon inoculation with Pythium irregulare, a common soil-borne oomycete. Infection of A. serpens gametophores by P. irregulare is characterized by localized cytoplasmic shrinkage within 34 h and chlorosis and necrosis within 7 d of inoculation. Within 24 h of a primary inoculation (induction), moss gametophores grown in culture became highly resistant to infection following subsequent inoculation (challenge) by the same pathogen. This increased resistance was a response to the pathogen itself and not to physical wounding. Treatment with β-1,3 glucan, a structural component of oomycete cell walls, was equally effective at triggering SAR. Our results demonstrate, for the first time, that this important defense mechanism exists in a non-vascular plant, and, together with previous studies, suggest that SAR arose prior to the divergence of vascular and non-vascular plants. In addition, this novel moss - pathogen culture system will be valuable for future characterization of the mechanism of SAR in moss, which is necessary for a better understanding of the evolutionary history of SAR in

Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata

NASA Technical Reports Server (NTRS)

Stewart, Patricia W.; Chapes, Stephen K.

2003-01-01

Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.

The Systemic Acquired Resistance Regulator OsNPR1 Attenuates Growth by Repressing Auxin Signaling through Promoting IAA-Amido Synthase Expression1[OPEN

PubMed Central

2016-01-01

Systemic acquired resistance is a long-lasting and broad-spectrum disease resistance to pathogens. Our previous study demonstrated that overexpression of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (OsNPR1), a master gene for systemic acquired resistance in rice (Oryza sativa), greatly enhanced resistance to bacterial blight caused by Xanthomonas oryzae pv oryzae. However, the growth and development of the OsNPR1 overexpression (OsNPR1-OX) plants were restrained, and the mechanism remained elusive. In this study, we dissected the OsNPR1-induced growth inhibition. We found that the OsNPR1-OX lines displayed phenotypes mimicking auxin-defective mutants, with decreases in root system, seed number and weight, internode elongation, and tiller number. Whole-genome expression analysis revealed that genes related to the auxin metabolism and signaling pathway were differentially expressed between the OsNPR1-OX and wild-type plants. Consistently, the indole-3-acetic acid (IAA) content was decreased and the auxin distribution pattern was altered in OsNPR1-OX plants. Importantly, we found that some GH3 family members, in particular OsGH3.8 coding IAA-amido synthetase, were constitutively up-regulated in OsNPR1-OX plants. Decreased OsGH3.8 expression by RNA interference could partially restore IAA level and largely rescue the restrained growth and development phenotypes but did not affect the disease resistance of OsNPR1-OX plants. Taken together, we revealed that OsNPR1 affects rice growth and development by disrupting the auxin pathway at least partially through indirectly up-regulating OsGH3.8 expression. PMID:27378815

Evaluation of the VeriStrat® serum protein test in patients with advanced squamous cell carcinoma of the lung treated with second-line afatinib or erlotinib in the phase III LUX-Lung 8 study.

PubMed

Gadgeel, Shirish; Goss, Glenwood; Soria, Jean-Charles; Felip, Enriqueta; Georgoulias, Vassilis; Lu, Shun; Cobo, Manuel; Syrigos, Konstantinos; Lee, Ki Hyeong; Göker, Erdem; Guclu, Salih Z; Isla, Dolores; Morabito, Alessandro; Dupuis, Nicholas; Bühnemann, Claudia; Krämer, Nicole; Solca, Flavio; Ehrnrooth, Eva; Ardizzoni, Andrea

2017-07-01

Identification of biomarkers associated with clinical benefit may be crucial in establishing optimal treatment choice for patients with squamous cell carcinoma (SCC) of the lung after first-line chemotherapy. In this study, the ability of the VeriStrat serum protein test to predict differential clinical benefit with afatinib versus erlotinib, and the association of VeriStrat status with clinical outcomes irrespective of EGFR-TKI used, was assessed in a retrospective analysis of the phase III LUX-Lung 8 trial. Pretreatment plasma samples were analyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Spectra were evaluated to assign a VeriStrat 'Good' (VS-G) or VeriStrat 'Poor' (VS-P) classification. Overall survival (OS), progression-free survival, and other endpoints were assessed with respect to pretreatment VeriStrat status; OS was the primary efficacy variable. Outcomes with other efficacy endpoints were similar. Of 795 patients randomized in LUX-Lung 8, 675 were classified (VS-G: 412; VS-P: 263). In the VS-G group, OS was significantly longer with afatinib versus erlotinib (HR 0.79 [95% CI: 0.63-0.98]). In the VS-P group, there was no significant difference in OS between afatinib and erlotinib (HR 0.90 [0.70-1.16]). However, there was no interaction between VeriStrat classification and treatment group for OS (p interaction =0.5303). OS was significantly longer in VS-G versus VS-P patients, both in the overall VeriStrat-classified population (HR 0.41 [0.35-0.49]) and afatinib-treated patients (HR 0.40 [0.31-0.51]). Multivariate analysis showed that VeriStrat was an independent predictor of OS in afatinib-treated patients, regardless of ECOG PS or best response to first-line chemotherapy. VS-G classification is strongly associated with favorable survival outcomes with either afatinib or erlotinib compared with VS-P classification. In VS-G patients, survival outcomes with afatinib are superior to those with erlotinib. Veri

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.

PubMed

Karachaliou, Niki; Codony-Servat, Jordi; Teixidó, Cristina; Pilotto, Sara; Drozdowskyj, Ana; Codony-Servat, Carles; Giménez-Capitán, Ana; Molina-Vila, Miguel Angel; Bertrán-Alamillo, Jordi; Gervais, Radj; Massuti, Bartomeu; Morán, Teresa; Majem, Margarita; Felip, Enriqueta; Carcereny, Enric; García-Campelo, Rosario; Viteri, Santiago; González-Cao, María; Morales-Espinosa, Daniela; Verlicchi, Alberto; Crisetti, Elisabetta; Chaib, Imane; Santarpia, Mariacarmela; Luis Ramírez, José; Bosch-Barrera, Joaquim; Felipe Cardona, Andrés; de Marinis, Filippo; López-Vivanco, Guillermo; Miguel Sánchez, José; Vergnenegre, Alain; Sánchez Hernández, José Javier; Sperduti, Isabella; Bria, Emilio; Rosell, Rafael

2015-12-07

BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.

Factors Associated with Adherence to and Treatment Duration of Erlotinib Among Patients with Non-Small Cell Lung Cancer.

PubMed

Hess, Lisa M; Louder, Anthony; Winfree, Katherine; Zhu, Yajun E; Oton, Ana B; Nair, Radhika

2017-06-01

In lung cancer, there is an increasing number of oral agents available for patients; however, little is known about the factors associated with adherence to and treatment duration on oral medications in non-small cell lung cancer (NSCLC). To evaluate the clinical and demographic factors associated with adherence and treatment discontinuation, respectively, to oral oncolytics among patients with NSCLC. A retrospective, claims-based analysis of the Humana Research Database supplemented with medical chart review was conducted among patients with NSCLC who started an oral oncolytic between January 1, 2008, and June 30, 2013. Patients were required to be enrolled at least 1 year before the start of oral oncolytics and have no evidence of any oral oncolytic use during this period. Logistic regression models and Cox proportional hazard models were used to identify predictors associated with medication adherence and treatment duration, respectively. Among all oral oncolytics, only the cohort starting on erlotinib had sufficient sample size (n = 1,452). A wide variety of factors were found to be associated with adherence. Low-income subsidy status, previous use of intravenous chemotherapy, and lower total baseline health care costs were significantly related to decreasing adherence (each P < 0.05). Additionally, increasing patient out-of-pocket cost was associated with decreasing adherence to erlotinib (P < 0.0001). Factors significantly related to longer treatment duration included low-income subsidy status (P < 0.001) and having Medicare insurance, (P = 0.0004), dual eligibility (Medicare and Medicaid, P = 0.007), and higher erlotinib out-of-pocket costs (P < 0.0001). There is a need for mechanisms to be in place to identify and address barriers to care. Future research should focus on evaluating and reducing any potential risk to patient outcomes that may be associated with low adherence to or shorter treatment duration on oral chemotherapy. This study was supported by

[Relationship between phenomenon of acquired activated protein C resistance and antiphospholipid antibodies in patients with systemic lupus erythematosus].

PubMed

Hu, Y Q; Chen, F P; Xie, Q Z

2001-10-28

To determine the occurrence of activated protein C resistance (APCR), to identify APCR is associated with thrombotic events (TEs), and acquired APCR is associated with the presence of antiphospholipid antibodies (APLAs) in 30 patients with systemic lupus erythematosus (SLE). Laboratory tests included dilute Russell's viper venom time assay for LA (dRVVT-LA), ELISA assay for ACL, APC sensitivity ratio, and factor V Leiden were detected by PCR-Mnl/I digestion. Acquired APCR was presented in 14(46.67%) of 30 patients. Factor V Leiden was not found in any patients. The incidence of TEs in the APCR-positive patients was significantly higher than that in the APCR-negative patients (42.85% vs 6.25%, P < 0.05). The incidence of TEs in the LA-positive patients was also significantly higher than that in the LA-negative patients (50% vs 11.1%, P < 0.05). The presence of either APCR or LAs is associated with one of the risk factors of TEs (P < 0.05). There is not a significant interaction between APCR and LAs in the association with TEs. Acquired APCR may not reflect the interference of LAs with the protein C pathway which may represent a mechanism of LA-associated TEs.

Diclofop-methyl affects microbial rhizosphere community and induces systemic acquired resistance in rice.

PubMed

Chen, Si; Li, Xingxing; Lavoie, Michel; Jin, Yujian; Xu, Jiahui; Fu, Zhengwei; Qian, Haifeng

2017-01-01

Diclofop-methyl (DM), a widely used herbicide in food crops, may partly contaminate the soil surface of natural ecosystems in agricultural area and exert toxic effects at low dose to nontarget plants. Even though rhizosphere microorganisms strongly interact with root cells, little is known regarding their potential modulating effect on herbicide toxicity in plants. Here we exposed rice seedlings (Xiushui 63) to 100μg/L DM for 2 to 8days and studied the effects of DM on rice rhizosphere microorganisms, rice systemic acquired resistance (SAR) and rice-microorganisms interactions. The results of metagenomic 16S rDNA Illumina tags show that DM increases bacterial biomass and affects their community structure in the rice rhizosphere. After DM treatment, the relative abundance of the bacterium genera Massilia and Anderseniella increased the most relative to the control. In parallel, malate and oxalate exudation by rice roots increased, potentially acting as a carbon source for several rhizosphere bacteria. Transcriptomic analyses suggest that DM induced SAR in rice seedlings through the salicylic acid (but not the jasmonic acid) signal pathway. This response to DM stress conferred resistance to infection by a pathogenic bacterium, but was not influenced by the presence of bacteria in the rhizosphere since SAR transcripts did not change significantly in xenic and axenic plant roots exposed to DM. The present study provides new insights on the response of rice and its associated microorganisms to DM stress. Copyright © 2016. Published by Elsevier B.V.

Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance.

PubMed

Lifshitz, Veronica; Priceman, Saul J; Li, Wenzhao; Cherryholmes, Gregory; Lee, Heehyoung; Makovski-Silverstein, Adar; Borriello, Lucia; DeClerck, Yves A; Yu, Hua

2017-11-01

Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow-mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhances etoposide-induced apoptosis in NB cells and abrogates EMDR, while overexpression of S1PR1 significantly protects NB cells from multidrug-induced apoptosis via activating JAK-STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA-approved drug and antagonist of S1PR1, dramatically sensitizes drug-resistant cells to etoposide. In summary, we identify S1PR1 as a critical target for reducing both EMDR and acquired chemoresistance in NB. Mol Cancer Ther; 16(11); 2516-27. ©2017 AACR . ©2017 American Association for Cancer Research.

Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study.

PubMed

Auliac, J B; Chouaid, C; Greillier, L; Greiller, L; Monnet, I; Le Caer, H; Falchero, L; Corre, R; Descourt, R; Bota, S; Berard, H; Schott, R; Bizieux, A; Fournel, P; Labrunie, A; Marin, B; Vergnenegre, A

2014-09-01

Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective. To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC. In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages. 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months. Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

PubMed

Gadgeel, Shirish M; Wozniak, Antoinette

2013-07-01

Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

PubMed

Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

2017-06-01

We report a HER2 T798I gatekeeper mutation in a patient with HER2 L869R -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2 L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3 E928G , also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2 T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 L869R but not HER2 L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2 L869R/T798I -induced signaling and cell growth. Acquisition of HER2 T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2 L869R is a driver mutation. HER2 T798I -mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2 -mutant breast cancer upon clinical progression on neratinib. We speculate that HER2 T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2 -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

Acute haematogenous community-acquired methicillin-resistant Staphylococcus aureus osteomyelitis in an adult: Case report and review of literature

PubMed Central

2012-01-01

Background Methicillin-resistant Staphylococcus aureus (MRSA) has of late emerged as a cause of community-acquired infections among immunocompetent adults without risk factors. Skin and soft tissue infections represent the majority of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clinical presentations, whilst invasive and life-threatening illness like necrotizing pneumonia, necrotizing fasciitis, pyomyositis, osteomyelitis and sepsis syndrome are less common. Although more widely described in the pediatric age group, the occurrence of CA-MRSA osteomyelitis in adults is an uncommonly reported entity. Case presentation We describe an invasive CA-MRSA infection in a 28 year-old previously healthy male, manifesting with bacteraemia, osteomyelitis of femur, pyomyositis and septic arthritis of the knee. Initially a preliminary diagnosis of osteosarcoma was suggested by imaging studies and patient underwent a bone biopsy. MRSA was subsequently isolated from blood cultures taken on day of admission, bone, tissue and pus cultures. Incision and drainage of abscess was performed and patient was treated with vancomycin, with fusidic acid added later. It took 6 months for the inflammatory markers to normalize, warranting 6-months of anti-MRSA therapy. Patient was a fervent deer hunter and we speculate that he acquired this infection from extensive direct contact with deer. Molecular characterization of this isolate showed that it belonged to multilocus sequence type (MLST) ST30 and exhibited the staphylococcal chromosome cassette mec (SCCmec) type IV, staphylococcus protein A (spa) type t019, accessory gene regulator (agr) type III and dru type dt10m. This strain harbored Panton-Valentine leukocidin (pvl) genes together with 3 other virulent genes; sei (enterotoxin), hlg (hemolysin) and fnbA (fibronectin binding protein). Conclusion This case study alerts physicians that beyond the most commonly encountered skin and soft tissue infections, pvl

Acute haematogenous community-acquired methicillin-resistant Staphylococcus aureus osteomyelitis in an adult: case report and review of literature.

PubMed

Dhanoa, Amreeta; Singh, Vivek Ajit; Mansor, Azura; Yusof, Mohd Yasim; Lim, King-Ting; Thong, Kwai-Lin

2012-10-25

Methicillin-resistant Staphylococcus aureus (MRSA) has of late emerged as a cause of community-acquired infections among immunocompetent adults without risk factors. Skin and soft tissue infections represent the majority of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clinical presentations, whilst invasive and life-threatening illness like necrotizing pneumonia, necrotizing fasciitis, pyomyositis, osteomyelitis and sepsis syndrome are less common. Although more widely described in the pediatric age group, the occurrence of CA-MRSA osteomyelitis in adults is an uncommonly reported entity. We describe an invasive CA-MRSA infection in a 28 year-old previously healthy male, manifesting with bacteraemia, osteomyelitis of femur, pyomyositis and septic arthritis of the knee. Initially a preliminary diagnosis of osteosarcoma was suggested by imaging studies and patient underwent a bone biopsy. MRSA was subsequently isolated from blood cultures taken on day of admission, bone, tissue and pus cultures. Incision and drainage of abscess was performed and patient was treated with vancomycin, with fusidic acid added later. It took 6 months for the inflammatory markers to normalize, warranting 6-months of anti-MRSA therapy. Patient was a fervent deer hunter and we speculate that he acquired this infection from extensive direct contact with deer.Molecular characterization of this isolate showed that it belonged to multilocus sequence type (MLST) ST30 and exhibited the staphylococcal chromosome cassette mec (SCCmec) type IV, staphylococcus protein A (spa) type t019, accessory gene regulator (agr) type III and dru type dt10m. This strain harbored Panton-Valentine leukocidin (pvl) genes together with 3 other virulent genes; sei (enterotoxin), hlg (hemolysin) and fnbA (fibronectin binding protein). This case study alerts physicians that beyond the most commonly encountered skin and soft tissue infections, pvl positive CA-MRSA can lead to invasive life

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib

PubMed Central

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L.

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug’s known mechanism of action. Also, the models predict each drug’s potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets. PMID:26107615

Role of PknB kinase in antibiotic resistance and virulence in community-acquired methicillin-resistant Staphylococcus aureus strain USA300.

PubMed

Tamber, Sandeep; Schwartzman, Joseph; Cheung, Ambrose L

2010-08-01

The regulation of cellular processes by eukaryote-like serine/threonine kinases is widespread in bacteria. In the last 2 years, several studies have examined the role of serine/threonine kinases in Staphylococcus aureus on cell wall metabolism, autolysis, and virulence, mostly in S. aureus laboratory isolates in the 8325-4 lineage. In this study, we showed that the pknB gene (also called stk1) of methicillin-resistant S. aureus (MRSA) strain COL and the community-acquired MRSA (CA-MRSA) strain USA300 is involved in cell wall metabolism, with the pknB mutant exhibiting enhanced sensitivity to beta-lactam antibiotics but not to other classes of antibiotics, including aminoglycosides, ciprofloxacin, bactrim, and other types of cell wall-active agents (e.g., vancomycin and bacitracin). Additionally, the pknB mutant of USA300 was found to be more resistant to Triton X-100-induced autolysis and also to lysis by lysostaphin. We also showed that pknB is a positive regulator of sigB activity, resulting in compromise in its response to heat and oxidative stresses. In association with reduced sigB activity, the expression levels of RNAII and RNAIII of agr and the downstream effector hla are upregulated while spa expression is downmodulated in the pknB mutant compared to the level in the parent. Consistent with an enhanced agr response in vitro, virulence studies of the pknB mutant of USA300 in a murine cutaneous model of infection showed that the mutant was more virulent than the parental strain. Collectively, our results have linked the pknB gene in CA-MRSA to antibiotic resistance, sigB activity, and virulence and have highlighted important differences in pknB phenotypes (virulence and sigB activity) between laboratory isolates and the prototypic CA-MRSA strain USA300.

Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer

PubMed Central

Bhattacharya, Bhaskar; Low, Sarah Hong Hui; Chong, Mei Ling; Chia, Dilys; Koh, King Xin; Sapari, Nur Sabrina; Kaye, Stanley; Hung, Huynh; Benoukraf, Touati; Soong, Richie

2016-01-01

Historically, understanding of acquired resistance (AQR) to combination treatment has been based on knowledge of resistance to its component agents. To test whether an altered drug interaction could be an additional factor in AQR to combination treatment, models of AQR to combination and single agent MEK and PI3K inhibitor treatment were generated. Combination indices indicated combination treatment of PI3K and MEK inhibitors remained synergistic in cells with AQR to single agent but not combination AQR cells. Differences were also observed between the models in cellular phenotypes, pathway signaling and drug cross-resistance. Genomics implicated TGFB2-EDN1 overexpression as candidate determinants in models of AQR to combination treatment. Supplementation of endothelin in parental cells converted synergism to antagonism. Silencing of TGFB2 or EDN1 in cells with AQR conferred synergy between PI3K and MEK inhibitor. These results highlight that AQR to combination treatment may develop through alternative mechanisms to those of single agent treatment, including a change in drug interaction. PMID:27081080

Outpatient pediatric community-acquired methicillin-resistant Staphylococcus aureus: a polymorphous clinical disease.

PubMed

Groner, Abraham; Laing-Grayman, Deborah; Silverberg, Nanette B

2008-02-01

Community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) presents numerous diagnostic and therapeutic problems for the outpatient physician, including the appropriate use of antibiotics and proper counseling of families on ways to prevent household spread. Most cases of CAMRSA in children involve soft tissue and skin infection, which is precisely the type of infection most likely to be diagnosed in a dermatology practice. We reviewed 8 pediatric cases of cutaneous CAMRSA that presented over 8 months. The 8 pediatric patients presented with one or more of the following: folliculitis (n=4), abscesses of the groin (n=3), impetiginized atopic dermatitis (AD)(n=2), pustules (n=2), bullous impetigo (n= 1), and nonbullous impetigo (n=1). Three caregivers of these children developed abscesses in exposed areas such as the forearm (n=3) and calf (n=1). The folliculitis cases involved the abdomen, groin and diaper region, buttocks, and inner thighs; the impetiginized AD did not differ from the distribution of the AD. The variety of clinical presentations and the spread in households represent a few of the many facets of CAMRSA in the pediatric dermatology outpatient setting.

MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib

PubMed Central

Yip, Cassandre; Foidart, Pierre; Somja, Joan; Truong, Alice; Lienard, Mehdi; Feyereisen, Emilie; Schroeder, Hélène; Gofflot, Stéphanie; Donneau, Anne-Françoise; Collignon, Joëlle; Delvenne, Philippe; Sounni, Nor Eddine; Jerusalem, Guy; Noël, Agnès

2017-01-01

Background: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. Methods: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. Results: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. Conclusions: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs. PMID:28196064

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

PubMed Central

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

PubMed Central

Chen, Qi; Quan, Qi; Ding, Lingyu; Hong, Xiangchan; Zhou, Ningning; Liang, Ying; Wu, Haiying

2015-01-01

Objectives Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy. Materials and Methods Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded. Results and Conclusion PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control. PMID:26172562

Phase I Study of Conformal Radiotherapy and Concurrent Full-Dose Gemcitabine With Erlotinib for Unresected Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, John M., E-mail: jrobertson@beaumont.edu; Margolis, Jeffrey; Jury, Robert P.

2012-02-01

Purpose: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. Methods and Materials: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m{sup 2}) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additionalmore » 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. Results: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. Conclusion: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.« less

Neutrophil Extracellular Trap (NET)-Mediated Killing of Pseudomonas aeruginosa: Evidence of Acquired Resistance within the CF Airway, Independent of CFTR

PubMed Central

Young, Robert L.; Malcolm, Kenneth C.; Kret, Jennifer E.; Caceres, Silvia M.; Poch, Katie R.; Nichols, David P.; Taylor-Cousar, Jennifer L.; Saavedra, Milene T.; Randell, Scott H.; Vasil, Michael L.; Burns, Jane L.; Moskowitz, Samuel M.; Nick, Jerry A.

2011-01-01

The inability of neutrophils to eradicate Pseudomonas aeruginosa within the cystic fibrosis (CF) airway eventually results in chronic infection by the bacteria in nearly 80 percent of patients. Phagocytic killing of P. aeruginosa by CF neutrophils is impaired due to decreased cystic fibrosis transmembrane conductance regulator (CFTR) function and virulence factors acquired by the bacteria. Recently, neutrophil extracellular traps (NETs), extracellular structures composed of neutrophil chromatin complexed with granule contents, were identified as an alternative mechanism of pathogen killing. The hypothesis that NET-mediated killing of P. aeruginosa is impaired in the context of the CF airway was tested. P. aeruginosa induced NET formation by neutrophils from healthy donors in a bacterial density dependent fashion. When maintained in suspension through continuous rotation, P. aeruginosa became physically associated with NETs. Under these conditions, NETs were the predominant mechanism of killing, across a wide range of bacterial densities. Peripheral blood neutrophils isolated from CF patients demonstrated no impairment in NET formation or function against P. aeruginosa. However, isogenic clinical isolates of P. aeruginosa obtained from CF patients early and later in the course of infection demonstrated an acquired capacity to withstand NET-mediated killing in 8 of 9 isolates tested. This resistance correlated with development of the mucoid phenotype, but was not a direct result of the excess alginate production that is characteristic of mucoidy. Together, these results demonstrate that neutrophils can kill P. aeruginosa via NETs, and in vitro this response is most effective under non-stationary conditions with a low ratio of bacteria to neutrophils. NET-mediated killing is independent of CFTR function or bacterial opsonization. Failure of this response in the context of the CF airway may occur, in part, due to an acquired resistance against NET-mediated killing by

Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.

PubMed

Yamaguchi, Fumihiro; Fukuchi, Kunihiko; Yamazaki, Yohei; Takayasu, Hiromi; Tazawa, Sakiko; Tateno, Hidetsugu; Kato, Eisuke; Wakabayashi, Aya; Fujimori, Mami; Iwasaki, Takuya; Hayashi, Makoto; Tsuchiya, Yutaka; Yamashita, Jun; Takeda, Norikazu; Kokubu, Fumio

2014-02-01

The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.

Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma.

PubMed

Johnson, Jennifer; Ascierto, Maria Libera; Mittal, Sandeep; Newsome, David; Kang, Liang; Briggs, Michael; Tanner, Kirk; Marincola, Francesco M; Berens, Michael E; Vande Woude, George F; Xie, Qian

2015-09-17

. Human and mouse microarrays maybe used to dissect the tumor-host interactions. Targeting MET in EGFR (amp) GBM may delay the acquired resistance developed during treatment with erlotinib.

An acquired HER2 T798I gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer

PubMed Central

Hanker, Ariella B.; Brewer, Monica Red; Sheehan, Jonathan H.; Koch, James P.; Sliwoski, Gregory R.; Nagy, Rebecca; Lanman, Richard; Berger, Michael F.; Hyman, David M.; Solit, David B.; He, Jie; Miller, Vincent; Cutler, Richard E.; Lalani, Alshad S.; Cross, Darren; Lovly, Christine M.; Meiler, Jens; Arteaga, Carlos L.

2017-01-01

We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. PMID:28274957

CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial.

PubMed

Sinn, Marianne; Bahra, Marcus; Liersch, Torsten; Gellert, Klaus; Messmann, Helmut; Bechstein, Wolf; Waldschmidt, Dirk; Jacobasch, Lutz; Wilhelm, Martin; Rau, Bettina M; Grützmann, Robert; Weinmann, Arndt; Maschmeyer, Georg; Pelzer, Uwe; Stieler, Jens M; Striefler, Jana K; Ghadimi, Michael; Bischoff, Sven; Dörken, Bernd; Oettle, Helmut; Riess, Hanno

2017-10-10

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m 2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.

[Topical problems of empiric therapy of community-acquired pneumonia in outpatient practice].

PubMed

Stepanova, I I; Chorbinskaya, S A; Baryshnikonva, G A; Nikiforova, N V; Pokutniy, N F; Zverkov, I V; Maslovskyi, L V; Kotenko, K V

2016-01-01

Community-acquired pneumonia is one of prevalent infectious respiratory diseases. Adequate treatment of community-acquired pneumonia, with consideration of the disease severity and microbial resistence, remains extremely topical. The article covers contemporary views of community-acquired pneumonia treatment standards. The authors described results of personal research aimed to study antibacterial treatment for community-acquired pneumonia on outpatient basis over 2004-2012, evaluated correspondence of the treatment to the national clinical recommendations.

Antimicrobial Resistance Gene Transfer in Drug Resistant Acinetobacter Species

USDA-ARS?s Scientific Manuscript database

Abstract: Antibiotic resistance is rapidly developing into one of the most formidable challenges for healthcare providers and researchers alike. To combat the rapid evolution of resistance, it will be important to uncover different mechanisms that bacteria use to acquire drug resistance genes. Acine...

Solithromycin for the treatment of community-acquired bacterial pneumonia.

PubMed

Viasus, Diego; Ramos, Oscar; Ramos, Leidy; Simonetti, Antonella F; Carratalà, Jordi

2017-01-01

Community-acquired pneumonia is a major public health problem worldwide. In recent years, there has been an increase in the frequency of resistance to the antimicrobials such as β-lactams or macrolides which have habitually been used against the causative pathogens. Solithromycin, a next-generation macrolide, is the first fluoroketolide with activity against most of the frequently isolated bacteria in community-acquired pneumonia, including typical and atypical bacteria as well as macrolide-resistant Streptococcus pneumoniae. Areas covered: A detailed assessment of the literature relating to the antimicrobial activity, pharmacokinetic/pharmacodynamic properties, efficacy, tolerability and safety of solithromycin for the treatment of community-acquired bacterial pneumonia Expert commentary: Recent randomized controlled phase II/III trials have demonstrated the equivalent efficacy of oral and intravenous solithromycin compared with fluoroquinolones in patients with lower mild-to-moderate respiratory infections, and have shown that systemic adverse events are comparable between solithromycin and alternative treatments. However, studies of larger populations which are able to identify infrequent adverse events are now needed to confirm these findings. On balance, current data supports solithromycin as a promising therapy for empirical treatment in adults with community-acquired bacterial pneumonia.

Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doherty, Kimberly R., E-mail: kimberly.doherty@quintiles.com; Wappel, Robert L.; Talbert, Dominique R.

2013-10-01

Tyrosine kinase inhibitors (TKi) have greatly improved the treatment and prognosis of multiple cancer types. However, unexpected cardiotoxicity has arisen in a subset of patients treated with these agents that was not wholly predicted by pre-clinical testing, which centers around animal toxicity studies and inhibition of the human Ether-à-go-go-Related Gene (hERG) channel. Therefore, we sought to determine whether a multi-parameter test panel assessing the effect of drug treatment on cellular, molecular, and electrophysiological endpoints could accurately predict cardiotoxicity. We examined how 4 FDA-approved TKi agents impacted cell viability, apoptosis, reactive oxygen species (ROS) generation, metabolic status, impedance, and ion channelmore » function in human cardiomyocytes. The 3 drugs clinically associated with severe cardiac adverse events (crizotinib, sunitinib, nilotinib) all proved to be cardiotoxic in our in vitro tests while the relatively cardiac-safe drug erlotinib showed only minor changes in cardiac cell health. Crizotinib, an ALK/MET inhibitor, led to increased ROS production, caspase activation, cholesterol accumulation, disruption in cardiac cell beat rate, and blockage of ion channels. The multi-targeted TKi sunitinib showed decreased cardiomyocyte viability, AMPK inhibition, increased lipid accumulation, disrupted beat pattern, and hERG block. Nilotinib, a second generation Bcr-Abl inhibitor, led to increased ROS generation, caspase activation, hERG block, and an arrhythmic beat pattern. Thus, each drug showed a unique toxicity profile that may reflect the multiple mechanisms leading to cardiotoxicity. This study demonstrates that a multi-parameter approach can provide a robust characterization of drug-induced cardiomyocyte damage that can be leveraged to improve drug safety during early phase development. - Highlights: • TKi with known adverse effects show unique cardiotoxicity profiles in this panel. • Crizotinib increases ROS

Cytotoxic chemotherapy may overcome the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy.

PubMed

Kanda, Shintaro; Horinouchi, Hidehito; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Sekine, Ikuo; Kunitoh, Hideo; Kubota, Kaoru; Tamura, Tomohide; Ohe, Yuichiro

2015-09-01

In the first-line treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been shown to yield a longer progression-free survival (PFS) rate than platinum-doublet chemotherapy; however, after the initial response, most patients develop resistance to the EGFR-TKIs. We hypothesized that the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong survival. We carried out a phase II study of the following first-line treatment for patients with advanced NSCLC harboring EGFR mutations. Gefitinib (250 mg) was administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Thereafter, gefitinib was re-started on day 134 and continued until disease progression. The primary endpoint was the two-year PFS rate. A total of 34 patients were enrolled. Of the 33 eligible patients and 12 achieved a two-year PFS. Thus, this therapeutic strategy met the criterion for usefulness. The 1-, 2-, 3-, and 5-year PFS rates were 67.0%, 40.2%, 36.9%, and 22.0%, respectively, and the median PFS was 19.5 months. The 1-, 2-, 3- and 5-year survival rates were 90.6%, 71.9%, 64.8%, and 36.5% respectively, and the median survival time was 48.0 months. These results indicate that the insertion of platinum-doublet chemotherapy might prevent the development of acquired resistance to EGFR-TKIs in patients with advanced NSCLC harboring EGFR mutations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

DTIC Science & Technology

2014-08-01

AWARD NUMBER: W81XWH-13-1-0227 TITLE: Deficient BIM Expression as a Mechanism of Intrinsic and...1Aug2013-31July2014 4. TITLE AND SUBTITLE Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to 5a. CONTRACT NUMBER...clinic. We had not had this capability when we applied for this award. We can now use these clinically relevant models to assess the expression of BIM

Rapid Response to High-Dose, Pulsatile Erlotinib in Afatinib-Refractory Leptomeningeal Carcinomatosis from Adenocarcinoma of the Lung: A Case Report.

PubMed

Fan, Frank S

2016-01-01

Leptomeningeal carcinomatosis occurred in an old female patient who was on a standard dose of afatinib for the treatment of her non-small cell lung cancer harboring an epidermal growth factor receptor gene mutation sensitive to tyrosine kinase inhibitors when extracranial lesions were still under control. Shifting to high-dose, pulsatile erlotinib dramatically saved her from the devastating condition in a very short period of time. Inadequate afatinib concentration in cerebrospinal fluid is reasonably suspected, and there is a call for clinical trials testing high-dose afatinib in leptomeningeal carcinomatosis.

[Mechanism of action and preclinical development of afatinib].

PubMed

Diz Taín, Pilar; González, Ana López; García-Palomo, Andrés

2016-04-01

Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors.

PubMed

Molife, L Rhoda; Yan, Li; Vitfell-Rasmussen, Joanna; Zernhelt, Adriane M; Sullivan, Daniel M; Cassier, Philippe A; Chen, Eric; Biondo, Andrea; Tetteh, Ernestina; Siu, Lillian L; Patnaik, Amita; Papadopoulos, Kyriakos P; de Bono, Johann S; Tolcher, Anthony W; Minton, Susan

2014-01-03

Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months. MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.

Principles of Antibiotic Management of Community-Acquired Pneumonia.

PubMed

Bender, Michael T; Niederman, Michael S

2016-12-01

Community-acquired pneumonia (CAP) encompasses a broad spectrum of disease severity and may require outpatient, inpatient, or intensive care management. Successful treatment hinges on expedient delivery of appropriate antibiotic therapy tailored to both the likely offending pathogens and the severity of disease. This review summarizes key principles in starting treatment and provides recommended empiric therapy regimens for each site of care. In addition, we discuss the antimicrobial and anti-inflammatory role macrolides play in CAP, as well as specific information for managing individual CAP pathogens such as community-acquired methicillin-resistant Staphylococcus aureus and drug-resistant Streptococcus pneumoniae . We also examine several novel antibiotics being developed for CAP and review the evidence guiding duration of therapy and current best practices for the transition of hospitalized patients from intravenous antibiotics to oral therapy. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Paired Phase II Studies of Erlotinib/Bevacizumab for Advanced Bronchioloalveolar Carcinoma or Never Smokers With Advanced Non-Small-cell Lung Cancer: SWOG S0635 and S0636 Trials.

PubMed

West, Howard L; Moon, James; Wozniak, Antoinette J; Mack, Philip; Hirsch, Fred R; Bury, Martin J; Kwong, Myron; Nguyen, Dorothy D; Moore, Dennis F; Miao, Jieling; Redman, Mary; Kelly, Karen; Gandara, David R

2018-01-01

Before mutation testing of the epidermal growth factor receptor (EGFR) gene was recognized as highly associated with the activity of EGFR tyrosine kinase inhibitors (TKIs), clinically defined patient populations with bronchioloalveolar carcinoma (BAC) and never smokers were identified as likely to benefit from EGFR TKIs. From preclinical and clinical data suggesting potentially improved efficacy with a combination of an EGFR TKI and the antiangiogenic agent bevacizumab, the Southwestern Oncology Group (SWOG) initiated paired phase II trials to evaluate the combination of erlotinib/bevacizumab in patients with advanced BAC (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636). Eligible patients with BAC or adenocarcinoma with BAC features (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636) received erlotinib 150 mg/day with bevacizumab 15 mg/kg until progression or prohibitive toxicity. Never smokers with BAC were preferentially enrolled to SWOG S0636. The primary endpoint for both trials was overall survival. A total of 84 patients were enrolled in the SWOG S0635 trial and 85 in the SWOG S0636 trial. The objective response rate was 22% (3% complete response) in the SWOG S0635 trial and 50% (38% confirmed; 3% complete response) in the SWOG S0636 trial. The median progression-free survival was 5 and 7.4 months in the S0635 and S0636 trials, respectively. The median overall survival was 21 and 29.8 months, respectively. Toxicity consisted mainly of rash and diarrhea in both trials. Although the field has moved toward molecular, rather than clinical, selection of patients as optimal candidates for EGFR TKI therapy, these results support the hypothesis that a subset of patients in whom erlotinib is particularly active could receive an incremental benefit from the addition of bevacizumab. Copyright © 2017 Elsevier Inc. All rights reserved.

Functional cooperation between HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR.

PubMed

Meng, Shuyan; Wang, Guorui; Lu, Yang; Fan, Zhen

2018-07-01

Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are important transcription factors regulating expression of genes involved in cell survival. HIF-1α and c-Jun are key components of HIF-1 and AP-1, respectively, and are regulated by epidermal growth factor receptor (EGFR)-mediated cell signaling and tumor microenvironmental cues. The roles of HIF-1α and c-Jun in development of resistance to EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) with activating mutation of EGFR have not been explored. In this study, we investigated the roles of HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR. Changes in HIF-1α protein and in total and phosphorylated c-Jun levels in relation to changes in total and phosphorylated EGFR levels before and after gefitinib treatment were measured using Western blot analysis in NSCLC cells sensitive or resistant to gefitinib. The impact of overexpression of a constitutively expressed HIF-1α (HIF-1α/ΔODD) or a constitutively active c-Jun upstream regulator (SEK1 S220E/T224D mutant) on cell response to gefitinib was also examined. The effect of pharmacological inhibition of SEK1-JNK-c-Jun pathway on cell response to gefitinib was evaluated. Downregulation of HIF-1α and total and phosphorylated c-Jun levels correlated with cell inhibitory response to gefitinib better than decrease in phosphorylated EGFR did in NSCLC cells with intrinsic or acquired resistance to gefitinib. Overexpression of HIF-1α/ΔODD or SEK1 S220E/T224D mutant conferred resistance to gefitinib. There exists a positive feed-forward regulation loop between HIF-1 and c-Jun. The JNK inhibitor SP600125 sensitized gefitinib-resistant NSCLC cells to gefitinib. HIF-1α and c-Jun functionally cooperate in development of resistance to gefitinib in NSCLC cells. The translational value of inhibiting HIF-1α/c-Jun cooperation in overcoming resistance to EGFR TKI

BATTLE: Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination

DTIC Science & Technology

2007-04-01

localization, which • The combination of erlotinib and Ad-dnIGF-1R synergistically inhibits the growth of tumors in xenograft mouse models . able outcomes...of erlotinib and Ad-dnIGF-1R synergistically inhibits the growth of tumors in xenograft mouse models . Specific Aim 2.3: To investigate the...biomarkers and adaptive randomization via hierarchical Bayes modeling . 2) To study the molecular mechanisms of response and resistance to targeted

Patients' Hand Washing and Reducing Hospital-Acquired Infection.

PubMed

Haverstick, Stacy; Goodrich, Cara; Freeman, Regi; James, Shandra; Kullar, Rajkiran; Ahrens, Melissa

2017-06-01

Hand hygiene is important to prevent hospital-acquired infections. Patients' hand hygiene is just as important as hospital workers' hand hygiene. Hospital-acquired infection rates remain a concern across health centers. To improve patients' hand hygiene through the promotion and use of hand washing with soap and water, hand sanitizer, or both and improve patients' education to reduce hospital-acquired infections. In August 2013, patients in a cardiothoracic postsurgical step-down unit were provided with individual bottles of hand sanitizer. Nurses and nursing technicians provided hand hygiene education to each patient. Patients completed a 6-question survey before the intervention, at hospital discharge and 1, 2, and 3 months after the intervention. Hospital-acquired infection data were tracked monthly by infection prevention staff. Significant correlations were found between hand hygiene and rates of infection with vancomycin-resistant enterococci ( P = .003) and methicillin-resistant Staphylococcus aureus ( P = .01) after the intervention. After the implementation of hand hygiene interventions, rates of both infections declined significantly and patients reported more staff offering opportunities for and encouraging hand hygiene. This quality improvement project demonstrates that increased hand hygiene compliance by patients can influence infection rates in an adult cardiothoracic step-down unit. The decreased infection rates and increased compliance with hand hygiene among the patients may be attributed to the implementation of patient education and the increased accessibility and use of hand sanitizer. ©2017 American Association of Critical-Care Nurses.

Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer.

PubMed

Wang, Ying-Nai; Lee, Heng-Huan; Chou, Chao-Kai; Yang, Wen-Hao; Wei, Yongkun; Chen, Chun-Te; Yao, Jun; Hsu, Jennifer L; Zhu, Cihui; Ying, Haoqiang; Ye, Yuanqing; Wang, Wei-Jan; Lim, Seung-Oe; Xia, Weiya; Ko, How-Wen; Liu, Xiuping; Liu, Chang-Gong; Wu, Xifeng; Wang, Huamin; Li, Donghui; Prakash, Laura R; Katz, Matthew H; Kang, Yaan; Kim, Michael; Fleming, Jason B; Fogelman, David; Javle, Milind; Maitra, Anirban; Hung, Mien-Chie

2018-04-09

Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families. Copyright © 2018 Elsevier Inc. All rights reserved.

Familial clustering of Taenia solium cysticercosis in the rural pigs of Mexico: hints of genetic determinants in innate and acquired resistance to infection.

PubMed

Sciutto, E; Martínez, J J; Huerta, M; Avila, R; Fragoso, G; Villalobos, N; de Aluja, A; Larralde, C

2003-10-20

In two rural villages of the state of Puebla, Mexico, where Taenia solium pig cysticercosis is highly endemic, 120 pairs of young out-bred piglets were used to assay what proved to be an effective synthetic peptide vaccine against naturally acquired cysticercosis. Because the piglets used were all sired by one of three distinct studs in many different out-bred sows, the prevalence and intensity of infection, as well as degree of protection conferred by the vaccine, could be related to each of the three stud families (A-C). The highest prevalence was found in the C family (25%), whilst the prevalence of B and A families were 21.6 and 4.4%, respectively. Familial clustering of cases was even more conspicuous in vaccinated pigs than in not-vaccinated ones: seven of the nine cysticercosis cases that occurred in the vaccinated group belonged to the C family (7/26) and two to the B family (2/23), whilst the vaccine rendered the A family totally resistant (0/71). Parasite numbers were also higher in the C family in both nai;ve and vaccinated pigs. Familial clustering of cases and of large parasite numbers in naive and vaccinated pigs hint to the relevance of their genetic background in their innate and acquired resistance to cysticercosis.

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

PubMed

Yoh, Kiyotaka; Doi, Toshihiko; Ohmatsu, Hironobu; Kojima, Takashi; Takahashi, Hideaki; Zenke, Yoshitaka; Wacheck, Volker; Enatsu, Sotaro; Nakamura, Takashi; Turner, Kellie; Uenaka, Kazunori

2016-10-01

Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.

Community-acquired bacterial meningitis.

PubMed

van de Beek, Diederik; Brouwer, Matthijs; Hasbun, Rodrigo; Koedel, Uwe; Whitney, Cynthia G; Wijdicks, Eelco

2016-11-03

Meningitis is an inflammation of the meninges and subarachnoid space that can also involve the brain cortex and parenchyma. It can be acquired spontaneously in the community - community-acquired bacterial meningitis - or in the hospital as a complication of invasive procedures or head trauma (nosocomial bacterial meningitis). Despite advances in treatment and vaccinations, community-acquired bacterial meningitis remains one of the most important infectious diseases worldwide. Streptococcus pneumoniae and Neisseria meningitidis are the most common causative bacteria and are associated with high mortality and morbidity; vaccines targeting these organisms, which have designs similar to the successful vaccine that targets Haemophilus influenzae type b meningitis, are now being used in many routine vaccination programmes. Experimental and genetic association studies have increased our knowledge about the pathogenesis of bacterial meningitis. Early antibiotic treatment improves the outcome, but the growing emergence of drug resistance as well as shifts in the distribution of serotypes and groups are fuelling further development of new vaccines and treatment strategies. Corticosteroids were found to be beneficial in high-income countries depending on the bacterial species. Further improvements in the outcome are likely to come from dampening the host inflammatory response and implementing preventive measures, especially the development of new vaccines.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.

PubMed

Bauman, Julie E; Duvvuri, Umamaheswar; Gooding, William E; Rath, Tanya J; Gross, Neil D; Song, John; Jimeno, Antonio; Yarbrough, Wendell G; Johnson, Faye M; Wang, Lin; Chiosea, Simion; Sen, Malabika; Kass, Jason; Johnson, Jonas T; Ferris, Robert L; Kim, Seungwon; Hirsch, Fred R; Ellison, Kimberly; Flaherty, John T; Mills, Gordon B; Grandis, Jennifer R

2017-03-23

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms ( P = 0.0014); however, no effect was seen with dasatinib alone ( P = 0.24). High baseline pMAPK expression was associated with response to erlotinib ( P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib ( P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

PubMed Central

Bauman, Julie E.; Duvvuri, Umamaheswar; Gooding, William E.; Rath, Tanya J.; Gross, Neil D.; Song, John; Jimeno, Antonio; Yarbrough, Wendell G.; Johnson, Faye M.; Wang, Lin; Chiosea, Simion; Sen, Malabika; Kass, Jason; Johnson, Jonas T.; Ferris, Robert L.; Kim, Seungwon; Hirsch, Fred R.; Ellison, Kimberly; Flaherty, John T.; Mills, Gordon B.

2017-01-01

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II–IVa HNSCC were randomized to 7–21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma. PMID:28352657

Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition.

PubMed

Stuhlmiller, Timothy J; Zawistowski, Jon S; Chen, Xin; Sciaky, Noah; Angus, Steven P; Hicks, Sean T; Parry, Traci L; Huang, Wei; Beak, Ju Youn; Willis, Monte S; Johnson, Gary L; Jensen, Brian C

2017-10-19

Most novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors are associated with cardiotoxicity, whereas others appear to be cardiosafe. The basis for this distinction is unclear, as are the molecular effects of kinase inhibitors in the heart. We administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multitargeted kinase inhibitors), or erlotinib (a cardiosafe epidermal growth factor receptor inhibitor) to mice daily for 2 weeks. We then compared the effects of these 3 kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all 3 kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using in vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective signal transducer and activator of transcription 3 pathway, as co-treatment with erlotinib and a signal transducer and activator of transcription inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation. Collectively our findings indicate that preclinical kinome and transcriptome profiling may predict the cardiotoxicity of novel kinase inhibitors, and suggest caution for the proposed therapeutic strategy of combined signal transducer and activator of transcription/epidermal growth factor receptor inhibition for cancer treatment. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

The Elicitor Protein AsES Induces a Systemic Acquired Resistance Response Accompanied by Systemic Microbursts and Micro-Hypersensitive Responses in Fragaria ananassa.

PubMed

Hael-Conrad, Verónica; Perato, Silvia Marisa; Arias, Marta Eugenia; Martínez-Zamora, Martín Gustavo; Di Peto, Pía de Los Ángeles; Martos, Gustavo Gabriel; Castagnaro, Atilio Pedro; Díaz-Ricci, Juan Carlos; Chalfoun, Nadia Regina

2018-01-01

The elicitor AsES (Acremonium strictum elicitor subtilisin) is a 34-kDa subtilisin-like protein secreted by the opportunistic fungus Acremonium strictum. AsES activates innate immunity and confers resistance against anthracnose and gray mold diseases in strawberry plants (Fragaria × ananassa Duch.) and the last disease also in Arabidopsis. In the present work, we show that, upon AsES recognition, a cascade of defense responses is activated, including: calcium influx, biphasic oxidative burst (O 2 ⋅- and H 2 O 2 ), hypersensitive cell-death response (HR), accumulation of autofluorescent compounds, cell-wall reinforcement with callose and lignin deposition, salicylic acid accumulation, and expression of defense-related genes, such as FaPR1, FaPG1, FaMYB30, FaRBOH-D, FaRBOH-F, FaCHI23, and FaFLS. All these responses occurred following a spatial and temporal program, first induced in infiltrated leaflets (local acquired resistance), spreading out to untreated lateral leaflets, and later, to distal leaves (systemic acquired resistance). After AsES treatment, macro-HR and macro-oxidative bursts were localized in infiltrated leaflets, while micro-HRs and microbursts occurred later in untreated leaves, being confined to a single cell or a cluster of a few epidermal cells that differentiated from the surrounding ones. The differentiated cells initiated a time-dependent series of physiological and anatomical changes, evolving to idioblasts accumulating H 2 O 2 and autofluorescent compounds that blast, delivering its content into surrounding cells. This kind of systemic cell-death process in plants is described for the first time in response to a single elicitor. All data presented in this study suggest that AsES has the potential to activate a wide spectrum of biochemical and molecular defense responses in F. ananassa that may explain the induced protection toward pathogens of opposite lifestyle, like hemibiotrophic and necrotrophic fungi.

Transdifferentiation between Luminal- and Basal-Type Cancer Cells

DTIC Science & Technology

2013-04-01

cancer patients have few choices of therapeutic agents. The MB231 cell line is a basal type cell line and is resistant to EGFR inhibitor erlotinib...mitotic inhibitor paclitaxel and DNA damaging agent cisplatin. However, over- expression of PKD1 makes the cell line sensitive to erlotinib and...approach will help to understand how PKD1 acts in basal-type cancer cells; (3) using existing small molecule inhibitors for PKD1 to treat breast cancer

Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience.

PubMed

Sullivan, Ivana; Planchard, David

2016-12-01

Patients with advanced epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) are particularly sensitive to treatment with first- or second-generation EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib and afatinib, which block the cell-signaling pathways that drive the growth of tumor cells. Unfortunately, the majority of patients develop resistance to them after a median duration of response of around 10 months, and in over half of these patients the emergence of the EGFR T790M resistance mutation is detected. Osimertinib is an oral, highly selective, irreversible inhibitor of both EGFR-activating mutations and the T790M-resistance mutation, while sparing the activity of wild-type EGFR This article reviews clinical trial development of osimertinib in patients with NSCLC, presenting efficacy and safety evidence for its value in the EGFR T790M mutation-positive population and in different settings, including patients with metastatic disease. The preclinical background of clinically acquired resistance to osimertinib is presented and the combination tactics being investigated in an attempt to circumvent this are addressed. © The Author(s), 2016.

Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience

PubMed Central

Sullivan, Ivana; Planchard, David

2016-01-01

Patients with advanced epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) are particularly sensitive to treatment with first- or second-generation EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib and afatinib, which block the cell-signaling pathways that drive the growth of tumor cells. Unfortunately, the majority of patients develop resistance to them after a median duration of response of around 10 months, and in over half of these patients the emergence of the EGFR T790M resistance mutation is detected. Osimertinib is an oral, highly selective, irreversible inhibitor of both EGFR-activating mutations and the T790M-resistance mutation, while sparing the activity of wild-type EGFR. This article reviews clinical trial development of osimertinib in patients with NSCLC, presenting efficacy and safety evidence for its value in the EGFR T790M mutation-positive population and in different settings, including patients with metastatic disease. The preclinical background of clinically acquired resistance to osimertinib is presented and the combination tactics being investigated in an attempt to circumvent this are addressed. PMID:27784815

Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer.

PubMed

Stachnik, Agnes; Yuen, Tony; Iqbal, Jameel; Sgobba, Miriam; Gupta, Yogesh; Lu, Ping; Colaianni, Graziana; Ji, Yaoting; Zhu, Ling-Ling; Kim, Se-Min; Li, Jianhua; Liu, Peng; Izadmehr, Sudeh; Sangodkar, Jaya; Scherer, Thomas; Mujtaba, Shiraz; Galsky, Matthew; Gomez, Jorge; Epstein, Solomon; Buettner, Christoph; Bian, Zhuan; Zallone, Alberta; Aggarwal, Aneel K; Haider, Shozeb; New, Maria I; Sun, Li; Narla, Goutham; Zaidi, Mone

2014-12-16

A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(ΔE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers.