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Egfr-tki resistance

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https://www.readbyqxmd.com/read/28088511/brief-report-egfr-l858m-l861q-cis-mutations-confer-selective-sensitivity-to-afatinib
#1
Jamie A Saxon, Lynette M Sholl, Pasi A Jänne
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with epidermal growth factor receptor (EGFR)-mutant lung cancers. However, the therapeutic efficacy of TKIs in patients with uncommon EGFR mutations remains unclear. METHODS: Next-generation sequencing was performed on a patient's lung adenocarcinoma tumor sample, revealing rare combined in cis (on the same allele) EGFR mutations. Stable Ba/F3 and NIH-3T3 cell lines harboring the mutations were established to investigate the effect of first, second, and third generation EGFR TKIs on cell proliferation by MTS assay and EGFR phosphorylation by Western blotting...
January 11, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28073786/phase-1-study-of-twice-weekly-pulse-dose-and-daily-low-dose-erlotinib-as-initial-treatment-for-patients-with-egfr-mutant-lung-cancers
#2
H A Yu, C Sima, D Feldman, L L Liu, B Vaitheesvaran, J Cross, C M Rudin, M G Kris, W Pao, F Michor, G J Riely
BACKGROUND: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. METHODS: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib...
October 25, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28061471/transformation-to-small-cell-carcinoma-as-an-acquired-resistance-mechanism-to-azd9291-a-case-report
#3
Lin Li, Hui Wang, Chao Li, Zheng Wang, Ping Zhang, Xu Yan
AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months' treatment of AZD9291 with hepatic metastasis...
January 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28040594/transcriptome-analysis-of-egfr-tyrosine-kinase-inhibitors-resistance-associated-long-noncoding-rna-in-non-small-cell-lung-cancer
#4
Pei Ma, Meiling Zhang, Fengqi Nie, Zebo Huang, Jing He, Wei Li, Liang Han
The non-small cell lung cancer (NSCLC) patients harbor mutations in the epidermal growth factor receptor (EGFR) can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib, and show improved progression-free survival. However, most of the patients who are initially responsive to EGFR TKIs with activating EGFR mutations eventually develop acquired resistance after long-term therapy, and are followed by disease progression. Recently, diverse mechanisms of acquired EGFR TKI resistance have been reported, but little is known about the role of long noncoding RNAs in EGFR TKIs resistance...
December 29, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28024692/synchronous-occurrence-of-squamous-cell-carcinoma-transformation-and-egfr-exon-20-s768i-mutation-as-a-novel-mechanism-of-resistance-in-egfr-mutated-lung-adenocarcinoma
#5
Lucia Longo, Maria Cecilia Mengoli, Federica Bertolini, Stefania Bettelli, Samantha Manfredini, Giulio Rossi
The occurrence of secondary EGFR mutation T790M in exon 20 and histologic "transformation" are common mechanisms underlying resistance to EGFR first- or second-generation tyrosine kinase inhibitors (TKI). We describe here on a hitherto unreported mechanism of EGFR TKI resistance synchronously combining squamous-cell carcinoma change and occurrence of the EGFR exon 20 S768I secondary mutation in a 43 year-old woman with stage IV adenocarcinoma harbouring EGFR exon 21 L858R mutation. After 8 months of response to gefitinib, the patient experienced EGFR TKI resistance and died of leptomeningeal neoplastic dissemination...
January 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28007627/clinical-outcome-of-alk-positive-non-small-cell-lung-cancer-nsclc-patients-with-de-novo-egfr-or-kras-co-mutations-receiving-tyrosine-kinase-inhibitors-tki
#6
Sabine Schmid, Oliver Gautschi, Sacha Rothschild, Michael Mark, Patrizia Froesch, Dirk Klingbiel, Hermann Reichegger, Wolfram Jochum, Joachim Diebold, Früh Martin
BACKGROUND: Non-small cell lung cancer (NSCLC) with de novo anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients (pts) are poorly understood. METHODS: Outcomes of pts with metastatic NSCLC de novo co- alterations of ALK/EGFR or ALK/KRAS detected by FISH (ALK) and sequencing (EGFR/KRAS) from six Swiss centres were analysed...
December 19, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28003335/the-ras-related-gtpase-rhob-confers-resistance-to-egfr-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer-via-an-akt-dependent-mechanism
#7
Olivier Calvayrac, Julien Mazières, Sarah Figarol, Claire Marty-Detraves, Isabelle Raymond-Letron, Emilie Bousquet, Magali Farella, Estelle Clermont-Taranchon, Julie Milia, Isabelle Rouquette, Nicolas Guibert, Amélie Lusque, Jacques Cadranel, Nathalie Mathiot, Ariel Savina, Anne Pradines, Gilles Favre
Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15...
December 21, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28002980/targeting-the-egfr-t790m-mutation-in-non-small-cell-lung-cancer
#8
Nicola Normanno, Monica Rosaria Maiello, Nicoletta Chicchinelli, Alessia Iannaccone, Claudia Esposito, Rossella De Cecio, Amelia D'alessio, Antonella De Luca
The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation...
December 23, 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28000387/a-comparison-of-ddpcr-and-arms-for-detecting-egfr-t790m-status-in-ctdna-from-advanced-nsclc-patients-with%C3%A2-acquired-egfr-tki-resistance
#9
Wenxian Wang, Zhengbo Song, Yiping Zhang
A sensitive and convenient method for detecting epidermal growth factor receptor (EGFR) T790M mutations from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance would be desirable to direct patient sequential treatment strategy. A comparison of two platforms for detecting EGFR mutations in plasma ctDNA was undertaken. Plasma samples and tumor samples were collected from patients with acquired EGFR-TKI resistance in Zhejiang Cancer Hospital from December 2014 to December 2015...
December 20, 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27992557/an-analysis-of-egfr-mutations-among-1506-cases-of-non-small-cell-lung-cancer-patients-in-guangxi-china
#10
Wen-E Wei, Nai-Quan Mao, Shu-Fang Ning, Ji-Lin Li, Hai-Zhou Liu, Tong Xie, Jian-Hong Zhong, Yan Feng, Chang-Hong Wei, Li-Tu Zhang
An association between epidermal growth factor receptor (EGFR) and clinical characteristics of non-small cell lung cancer (NSCLC) was reported ten years ago. In addition, a different type of relationship was seen in different ethic races. However, the relationship between these factors is not well understood in the Guangxi province. Up to now, there are only very limited data on the association of TTF1/EGFR protein positivity and EGFR mutation status in NSCLC. This study aims to investigate the role of EGFR gene mutation status on the clinical characteristics and the relationship with TTF-1/EGFR protein positivity of patients with NSCLC in Guangxi, China...
2016: PloS One
https://www.readbyqxmd.com/read/27989877/chinese-herbal-medicine-fuzheng-kang-ai-decoction-sensitized-the-effect-of-gefitinib-on-inhibition-of-human-lung-cancer-cells-through-inactivating-pi3-k-akt-mediated-suppressing-muc1-expression
#11
Longmei Li, SuMei Wang, Fang Zheng, WanYin Wu, Swei Sunny Hann
ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) Fuzheng Kang-Ai (FZKA for short) decoction has been used as adjuvant treatment strategies in lung cancer patients for decades. However, the molecular mechanism underlying the therapeutic potential especially in sensitizing the effect of EGFR-TKI gefitinib has not been well elucidated. MATERIALS AND METHODS: Cell viability was detected by MTT assay. Cell cycle distribution was detected by flow cytometry...
October 28, 2016: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/27987577/coexistence-of-p16-cdkn2a-homozygous-deletions-and-activating-egfr-mutations-in-lung-adenocarcinoma-patients-signifies-a-poor-response-to-egfr-tkis
#12
Juhong Jiang, Yingying Gu, Jing Liu, Ruibin Wu, Lin Fu, Jin Zhao, Yubao Guan
OBJECTIVES: Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations. The goal of this study was to determine whether p16/CDKN2A homozygous deletion (HD) is associated with primary resistance to EGFR-TKIs in lung adenocarcinoma patients with EGFR activating mutations...
December 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27986747/histone-deacetylase-3-inhibition-overcomes-bim-deletion-polymorphism-mediated-osimertinib-resistance-in-egfr-mutant-lung-cancer
#13
Azusa Tanimoto, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Tadaaki Yamada, Xavier Roca, Sin Tiong Ong, Seiji Yano
PURPOSE: The BIM deletion polymorphism is associated with apoptosis resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), 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...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27980215/guide-to-detecting-epidermal-growth-factor-receptor-egfr-mutations-in-ctdna-of-patients-with-advanced-non-small-cell-lung-cancer
#14
REVIEW
Nicola Normanno, Marc G Denis, Kenneth S Thress, Marianne Ratcliffe, Martin Reck
Cancer treatment is evolving towards therapies targeted at specific molecular abnormalities that drive tumor growth. Consequently, to determine which patients are eligible, accurate assessment of molecular aberrations within tumors is required. Obtaining sufficient tumor tissue for molecular testing can present challenges; therefore, circulating free tumor-derived DNA (ctDNA) found in blood plasma has been proposed as an alternative source of tumor DNA. The diagnostic utility of ctDNA for the detection of epidermal growth factor receptor (EGFR) mutations harbored in tumors of patients with advanced non-small-cell lung cancer (NSCLC) is supported by the results of several large studies/meta-analyses...
December 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27978873/-relationship-between-id1-and-egfr-tki-resistance-%C3%A2-in-non-small-cell-lung-cancer
#15
Yuchen Bao, Yinmin Zhao, Bin Chen, Jie Luo, Qinfang Deng, Hui Sun, Boxiong Xie, Songwen Zhou
BACKGROUND: Non-small cell lung cancer (NSCLC) presents the highest morbidity and mortality among malignant tumors worldwide. The overall effective rate of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is 30% to 40%, and PFS (progression-free sruvival) is 12 months. However, EGFR-TKI resistance is typical in clinical observations, and this phenomenon significantly affects tumor suppression. To overcome this resistance, a new prognostic factor associated with lung cancer drug resistance should be discovered...
December 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/27969527/ps01-60-ph-ib-ii-trial-of-inc280-%C3%A2-erlotinib-vs-platinum-pemetrexed-in-adult-pts-with-egfr-mutated-cmet-amplified-egfr-tki-resistant-advanced-nsclc-topic-medical-oncology
#16
Igor I Rybkin, Egbert Smit, Hans-Georg Kopp, Dong-Wan Kim, Alexander Spira, Alfredo Berruti, Dae Ho Lee, Noemí Reguart, Mikhail Akimov, Karl Schumacher, Allison Upalawanna, Matthew Squires, Daniel S-W Tan
No abstract text is available yet for this article.
November 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27959700/osimertinib-or-platinum-pemetrexed-in-egfr-t790m-positive-lung-cancer
#17
Tony S Mok, Yi-Long Wu, Myung-Ju Ahn, Marina C Garassino, Hye R Kim, Suresh S Ramalingam, Frances A Shepherd, Yong He, Hiroaki Akamatsu, Willemijn S M E Theelen, Chee K Lee, Martin Sebastian, Alison Templeton, Helen Mann, Marcelo Marotti, Serban Ghiorghiu, Vassiliki A Papadimitrakopoulou
Background Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. Methods In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed...
December 6, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27916828/enhancing-anticancer-effect-of-gefitinib-across-the-blood-brain-barrier-model-using-liposomes-modified-with-one-%C3%AE-helical-cell-penetrating-peptide-or-glutathione-and-tween-80
#18
Kuan-Hung Lin, Shu-Ting Hong, Hsiang-Tsui Wang, Yu-Li Lo, Anya Maan-Yuh Lin, James Chih-Hsin Yang
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to treat BM is the limited penetration of anticancer drugs across the blood-brain barrier (BBB). In the present study, we utilized gefitinib-loaded liposomes with different modifications to improve gefitinib delivery across the in vitro BBB model of bEnd...
November 29, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27912760/update-on-recent-preclinical-and-clinical-studies-of-t790m-mutant-specific-irreversible-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors
#19
REVIEW
Bin-Chi Liao, Chia-Chi Lin, Jih-Hsiang Lee, James Chih-Hsin Yang
The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy...
December 3, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27910964/osimertinib-a-third-generation-tyrosine-kinase-inhibitor-targeting-non-small-cell-lung-cancer-with-egfr-t790m-mutations
#20
C E McCoach, A Jimeno
Oncogenic driver mutations in the epidermal growth factor receptor (EGFR) gene have provided a focus for effective targeted therapy. Unfortunately, all patients eventually develop resistance to frontline therapy with EGFR tyrosine kinase inhibitors (TKIs). The majority of patients develop a large subclonal population of tumor cells with a T790M mutation that renders these cells resistant to first-generation TKIs. Osimertinib is a third-generation EGFR TKI that was designed to overcome resistance from T790M mutations...
October 2016: Drugs of Today
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