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Egfr-tki resistance

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https://www.readbyqxmd.com/read/29221264/continuation-of-gefitinib-plus-chemotherapy-prolongs-progression-free-survival-in-advanced-non-small-cell-lung-cancer-patients-who-get-acquired-resistance-to-gefitinib-without-t790m-mutations
#1
Ting Ding, Fei Zhou, Xiaoxia Chen, Shijia Zhang, Yinan Liu, Hui Sun, Shengxiang Ren, Xuefei Li, Chao Zhao, Heyong Wang, Caicun Zhou
Background: Aimed to identify the benefit population from continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), this study investigated the efficacy of continuation of EGFR-TKIs plus chemotherapy beyond the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) according to different progression modes and T790M mutational status. Methods: From November 2009 to July 2015, 630 patients with advanced non-small cell lung cancer (NSCLC) receiving gefitinib as initial EGFR-TKI treatment were screened in Shanghai Pulmonary Hospital...
September 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/29215723/high-cholesterol-in-lipid-rafts-reduces-the-sensitivity-to-egfr-tki-therapy-in-non-small-cell-lung-cancer
#2
Qiufang Chen, Zhenzhen Pan, Min Zhao, Qin Wang, Chen Qiao, Liyun Miao, Xuansheng Ding
Overcoming EGFR-TKI resistant which has the initial enthusiasm over substantial clinical responses is a formidable challenge on nowadays. In this study, we showed that cholesterol level in lipid rafts in gefitinib resistant non-small cell lung cancer (NSCLC) cell lines was remarkably higher than gefitinib sensitive cell line, and depletion of cholesterol increase gefitinib sensitivity. Furthermore, Cholesterol-depleted enhanced gefitinib inhibit phosphorylation of EGFR, Akt-1, MEK1/2 and ERK1/2 and these were reversed in cholesterol add-back experiments...
December 7, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29212495/feasibility-of-tissue-re-biopsy-in-non-small-cell-lung-cancers-resistant-to-previous-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-therapies
#3
Sakurako Uozu, Kazuyoshi Imaizumi, Teppei Yamaguchi, Yasuhiro Goto, Kenji Kawada, Tomoyuki Minezawa, Takuya Okamura, Ken Akao, Masamichi Hayashi, Sumito Isogai, Mitsushi Okazawa, Naozumi Hashimoto, Yoshinori Hasegawa
BACKGROUND: When epidermal growth factor receptor (EGFR) gene mutation-positive non-small cell lung cancer (NSCLC) acquires resistance to the initial tyrosine kinase inhibitor (TKI) treatment, reassessing the tumor DNA by re-biopsy is essential for further treatment selection. However, the process of TKI-sensitive tumor re-progression and whether re-biopsy is possible in all cases of acquired resistance to EGFR-TKI remain unclear. METHODS: We retrospectively analyzed data from 69 consecutive patients with EGFR gene mutation-positive advanced NSCLC who had been treated with EGFR-TKI and exhibited disease relapse after initial disease remission...
December 6, 2017: BMC Pulmonary Medicine
https://www.readbyqxmd.com/read/29212192/vorinostat-and-metformin-sensitize-egfr-tki-resistant-nsclc-cells-via-bim-dependent-apoptosis-induction
#4
Hengyi Chen, Yubo Wang, Caiyu Lin, Conghua Lu, Rui Han, Lin Jiao, Li Li, Yong He
There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin - a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207200/effect-of-tw37-on-the-growth-of-h1975-egfr%C3%A2-tki%C3%A2-resistant-lung-cancer-cells-and-its-underlying-mechanisms
#5
Jixian Liu, Xinhuang Yao, Da Wu, Yiwang Ye, Qiang Wu, Suyue Liu, Hao Wu
Previous studies have suggested that the B‑cell lymphoma 2 (Bcl‑2) inhibitor, TW37, may induce apoptosis of the non‑small cell lung cancer cell line, H1975/epidermal growth factor receptor‑tyrosine kinase inhibitor (EGFR‑TKI), which exhibits secondary resistance to EGFR‑TKI. However, the effects of TW37 on H1975/EGFR‑TKI cells remain unclear. The aim of the present study was to investigate the effects of TW37 on the growth of H1975/EGFR‑TKI cells and explore the underlying mechanisms. An in vitro study was performed, whereby H1975/EGFR‑TKI cells were treated with serially increasing concentrations of TW37...
November 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29202823/trastuzumab-emtansine-delays-and-overcomes-resistance-to-the-third-generation-egfr-tki-osimertinib-in-nsclc-egfr-mutated-cell-lines
#6
Silvia La Monica, Daniele Cretella, Mara Bonelli, Claudia Fumarola, Andrea Cavazzoni, Graziana Digiacomo, Lisa Flammini, Elisabetta Barocelli, Roberta Minari, Nadia Naldi, Pier Giorgio Petronini, Marcello Tiseo, Roberta Alfieri
BACKGROUND: Osimertinib is a third-generation EGFR-TKI with a high selective potency against T790M-mutant NSCLC patients. Considering that osimertinib can lead to enhanced HER-2 expression on cell surface and HER-2 overexpression is a mechanism of resistance to osimertinib, this study was addressed to investigate the potential of combining osimertinib with trastuzumab emtansine (T-DM1) in order to improve the efficacy of osimertinib and delay or overcome resistance in NSCLC cell lines with EGFR activating mutation and with T790M mutation or HER-2 amplification...
December 4, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29200719/anti-cancer-effects-of-polyphenolic-compounds-in-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-resistant-non-small-cell-lung-cancer
#7
Hyungmin Jeong, Ai N H Phan, Jong-Whan Choi
Background: Polyphenolic phytochemicals are natural compounds, easily found in fruits and vegetables. Importantly, polyphenols have been intensively studied as excellent antioxidant activity which contributes to anticancer function of the natural compounds. Lung cancer has been reported to mainly account for cancer-related deaths in the world. Moreover, epidermal growth factor receptor tyrosine kinase inhibitor (TKI) resistance is one of the biggest issues in cancer treatment, especially in nonsmall cell lung cancer (NSCLC)...
October 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/29199595/epidermal-growth-factor-receptor-tyrosine-kinase-a-potential-target-in-treatment-of-non-small-cell-lung-carcinoma
#8
REVIEW
Venugopal Vinod Prabhu, Niranjali Devaraj
Lung cancer is responsible for 1.6 million deaths. Approximately 80%-85% of lung cancers are of the non-small-cell variety, which includes squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma. Knowing the stage of cancer progression is a requisite for determining which management approach-surgery, chemotherapy, radiotherapy, and/or immunotherapy-is optimal. Targeted therapeutic approaches with antiangiogenic monoclonal antibodies or tyrosine kinase inhibitors are one option if tumors harbor oncogene mutations...
2017: Journal of Environmental Pathology, Toxicology and Oncology
https://www.readbyqxmd.com/read/29190911/acquisition-of-egfr-tki-resistance-and-emt-phenotype-is-linked-with-activation-of-igf1r-nf-%C3%AE%C2%BAb-pathway-in-egfr-mutant-nsclc
#9
Ling Li, Xiajing Gu, Jinnan Yue, Qingnan Zhao, Dacheng Lv, Hongzhuan Chen, Lu Xu
Epithelial-mesenchymal transition (EMT) is clinically associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small cell lung cancers (NSCLC). However, the mechanisms promoting EMT in EGFR TKI-resistant NSCLC have not been fully elucidated. Previous studies have suggested that IGF1R signaling is involved in both acquired EGFR TKI resistance in NSCLC and induction of EMT in some types of tumor. In this study, we further explored the role of the IGF1R signaling in the acquisition of EMT phenotype associated with EGFR TKI resistance in mutant-EGFR NSCLC...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29180936/osimertinib-effective-treatment-of-nsclc-with-activating-egfr-mutations-after-progression-on-egfr-tyrosine-kinase-inhibitors
#10
Marcin Skrzypski, Amelia Szymanowska-Narloch, Rafał Dziadziuszko
Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib...
2017: Contemporary Oncology Współczesna Onkologia
https://www.readbyqxmd.com/read/29179454/plasma-microrna-alterations-between-egfr-activating-mutational-nsclc-patients-with-and-without-primary-resistance-to-tki
#11
Yihan Ma, Xiaoyan Pan, Peiqi Xu, Yanjun Mi, Wenyi Wang, Xiaoting Wu, Qi He, Xinli Liu, Weiwei Tang, Han-Xiang An
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have obtained excellent therapeutic effects against non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, some patients have exhibited primary resistance which becomes a major obstacle in effective treatment of NSCLC. The mechanisms of EGFR-TKIs resistance involved are still poorly understood. Many studies suggest that miRNAs play an important role in regulating drug sensitivity of EGFR-TKIs. The aim of the present study was to examine differentially expressed miRNAs in plasma between EGFR-TKIs sensitive and EGFR-TKIs primary resistance patients...
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163769/yap1-is-essential-for-tumor-growth-and-is-a-potential-therapeutic-target-for-egfr-dependent-lung-adenocarcinomas
#12
Ting-Fang Lee, Yu-Chi Tseng, Wei-Chin Chang, Yi-Chen Chen, Yu-Rung Kao, Teh-Ying Chou, Chao-Chi Ho, Cheng-Wen Wu
Epidermal growth factor receptor (EGFR) mutations are found in lung adenocarcinomas leading to tumor cells proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) that block EGFR activity are effective therapeutics for EGFR-mutant lung adenocarcinoma patients, but TKI-resistance inevitably occurs. The YES-associated protein (YAP1) transcription coactivator has been implicated as an oncogene and is amplified in human cancers and provides tumor cells strong proliferation and survival cues. This study investigated the roles of YAP1 in lung adenocarcinoma by exploring its regulation and functions mediated by EGFR signaling...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156777/patients-with-nsclc-may-display-a-low-ratio-of-p-t790m-vs-activating-egfr-mutations-in-plasma-at-disease-progression-implications-for-personalised-treatment
#13
Marzia Del Re, Paola Bordi, Iacopo Petrini, Eleonora Rofi, Francesca Mazzoni, Lorenzo Belluomini, Enrico Vasile, Giuliana Restante, Francesco Di Costanzo, Alfredo Falcone, Antonio Frassoldati, Ron H N van Schaik, Christi M J Steendam, Antonio Chella, Marcello Tiseo, Riccardo Morganti, Romano Danesi
Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29151965/combined-inhibitions-of-glycolysis-and-akt-autophagy-can-overcome-resistance-to-egfr-targeted-therapy-of-lung-cancer
#14
Mingtong Ye, Sufan Wang, Ting Wan, Rui Jiang, Yun Qiu, Lei Pei, Nengzhi Pang, Yuanling Huang, Yufeng Huang, Zhenfeng Zhang, Lili Yang
Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29151955/continuation-of-tyrosine-kinase-inhibitor-is-associated-with-survival-benefit-in-nsclc-patients-with-exon-19-deletion-after-solitary-progression
#15
Feifei Na, Jie Zhang, Lei Deng, Xiaojuan Zhou, Lin Zhou, Bingwen Zou, Min Yu, Yanying Li, Jianxin Xue, Yongmei Liu
INTRODUCTION: The benefit and selection criteria of continuing tyrosine kinase inhibitor (TKI) after secondary resistance in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutation remain largely unknown. This study was designed to investigate the role and predictive factors of TKI continuation in patients with solitary progression. METHODS: We retrospectively analyzed NSCLCs treated with first generation of TKI from June 2009 to October 2014 in our cancer center...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29151359/osimertinib-in-untreated-egfr-mutated-advanced-non-small-cell-lung-cancer
#16
Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste, Thanyanan Reungwetwattana, Busyamas Chewaskulyong, Ki Hyeong Lee, Arunee Dechaphunkul, Fumio Imamura, Naoyuki Nogami, Takayasu Kurata, Isamu Okamoto, Caicun Zhou, Byoung Chul Cho, Ying Cheng, Eun Kyung Cho, Pei Jye Voon, David Planchard, Wu-Chou Su, Jhanelle E Gray, Siow-Ming Lee, Rachel Hodge, Marcelo Marotti, Yuri Rukazenkov, Suresh S Ramalingam
Background Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Methods In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily)...
November 18, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29143497/detection-and-monitoring-of-driver-mutations-by-next-generation-sequencing-in-squamous-cell-lung-cancer-patient-and-possible-predictive-biomarker-of-third-generation-egfr-tyrosine-kinase-inhibitors
#17
Xiaoyan Shen, Jie Shen, Hang Zhang, Yuxin Cheng, Yang Yang, Jiahui Gao, Yu Zhang, Rutian Li, Baorui Liu, Lifeng Wang
Driver mutation detection and the development of targeted drugs have significantly improved survival of advanced lung adenocarcinoma patients with driver mutations. However, we still lack understanding of druggable mutations in patients with advanced squamous cell lung cancer (SQCLC). Less than 10% of SQCLC patients have EGFR gene mutations, thus we have limited knowledge of biological molecular changes with first generation EGFR-tyrosine kinase inhibitor (TKI) resistance. We report a case of an SQCLC patient treated with first-line platinum-doublet chemotherapy...
November 16, 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/29123416/frequency-and-clinical-relevance-of-egfr-mutations-and-eml4-alk-translocations-in-octogenarians-with-non-small-cell-lung-cancer
#18
Amanda Tufman, Kathrin Kahnert, Thomas Duell, Diego Kauffmann-Guerrero, Katrin Milger, Christian Schneider, Julia Stump, Zulfiya Syunyaeva, Rudolf Maria Huber, Simone Reu
Background: Tyrosine kinase inhibitors (TKIs) have improved response rates in some patients with non-small cell lung cancer (NSCLC), and testing for EGFR mutation and ALK translocation is recommended for all patients with advanced lung adenocarcinoma. The frequency of driver mutations in elderly and very elderly patients has not been described. Patients and methods: We reviewed EGFR and ALK in patients over the age of 70 years diagnosed and treated at our center in 2015 (subgroups: 70-74, 75-79 and >80 years)...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29121501/does-c-met-remain-a-rational-target-for-therapy-in-patients-with-egfr-tki-resistant-non-small-cell-lung-cancer
#19
REVIEW
Yi-Long Wu, Ross Andrew Soo, Giuseppe Locatelli, Uz Stammberger, Giorgio Scagliotti, Keunchil Park
Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5-20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c-Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC...
December 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29120087/histological-evolution-from-primary-lung-adenocarcinoma-harboring-egfr-mutation-to-high-grade-neuroendocrine-carcinoma
#20
Jikai Zhao, Jinchen Shao, Ruiying Zhao, Rong Li, Keke Yu, Lei Zhu, Jie Zhang
BACKGROUND: Although patients with EGFR mutated lung adenocarcinoma benefit greatly from tyrosine kinase inhibitors (TKIs), they inevitably develop acquired resistance after an average of 10-14 months of continuous treatment. METHODS: We retrospectively analyzed the clinical and histopathological data of eight patients with primary lung adenocarcinoma harboring EGFR mutations that transformed into high-grade neuroendocrine carcinoma after TKI therapy. Morphology scanning for neuroendocrine differentiation and immunohistochemistry for neuroendocrine markers CD56, chromogranin, and synaptophysin were performed on primary adenocarcinoma tissues and repeated biopsies...
November 9, 2017: Thoracic Cancer
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