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T790m and met

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https://www.readbyqxmd.com/read/29789220/adaura-phase-iii-double-blind-randomized-study-of-osimertinib-versus-placebo-in-egfr-mutation-positive-early-stage-nsclc-after-complete-surgical-resection
#1
Yi-Long Wu, Roy S Herbst, Helen Mann, Yuri Rukazenkov, Marcelo Marotti, Masahiro Tsuboi
INTRODUCTION: Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non-small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study. PATIENTS AND METHODS: Study entry will be limited to adults aged ≥ 18 years (and in Japan and Taiwan, age ≥ 20 years) with primary nonsquamous stage IB-IIIA non-small-cell lung cancer with central confirmation of an EGFR exon 19 deletion or L858R mutation...
May 1, 2018: Clinical Lung Cancer
https://www.readbyqxmd.com/read/29758406/molecular-dynamics-guided-development-of-indole-based-dual-inhibitors-of-egfr-t790m-and-c-met
#2
Pankaj Kumar Singh, Om Silakari
Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases...
April 25, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29721209/radiotherapy-increases-plasma-levels-of-tumoral-cell-free-dna-in-non-small-cell-lung-cancer-patients
#3
Shun-Ichiro Kageyama, Keiji Nihei, Katsuyuki Karasawa, Takeshi Sawada, Fumiaki Koizumi, Shigeo Yamaguchi, Shunsuke Kato, Hidehiro Hojo, Atsuhi Motegi, Katsuya Tsuchihara, Tetsuo Akimoto
We investigated the plasma levels of tumor-specific cell-free DNA (cfDNA) in 17 stage I-II (early) and IV (advanced) non-small cell lung cancer (NSCLC) patients who underwent radiotherapy. Digital polymerase chain reaction (PCR) and targeted sequencing showed that total and tumor-specific cfDNA levels increased in response to radiotherapy in both early- and advanced-stage NSCLC patients. We detected high copy numbers of epidermal growth factor receptor mutations (L858R and T790M) in the cfDNA samples from stage IV NSCLC patients who underwent stereotactic body radiation therapy to treat brain metastasis related to tyrosine kinase inhibitor (TKI) treatment failure...
April 10, 2018: Oncotarget
https://www.readbyqxmd.com/read/29713646/mutational-profiling-of-non-small-cell-lung-cancer-resistant-to-osimertinib-using-next-generation-sequencing-in-chinese-patients
#4
Keke Nie, Haiping Jiang, Chunling Zhang, Chuanxin Geng, Xiajuan Xu, Ling Zhang, Hao Zhang, Zhongfa Zhang, Ketao Lan, Youxin Ji
Purpose: To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods: Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS)...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29626621/first-in-human-phase-i-study-of-ac0010-a-mutant-selective-egfr-inhibitor-in-non-small-cell-lung-cancer-safety-efficacy-and-potential-mechanism-of-resistance
#5
Yuxiang Ma, Xin Zheng, Hongyun Zhao, Wenfeng Fang, Yang Zhang, Jieying Ge, Lu Wang, Weicong Wang, Ji Jiang, Shaokun Chuai, Zhou Zhang, Wanhong Xu, Xiao Xu, Pei Hu, Li Zhang
INTRODUCTION: AC0010 is a mutation-selective, third-generation EGFR tyrosine kinase inhibitor (TKI). This first-in-human phase I trial determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AC0010 in patients with advanced or recurrent NSCLC and acquired resistance to the first-generation EGFR-TKI. METHODS: Patients received escalating daily doses of AC0010 (50 to 600 mg) throughout 28-day cycles...
April 4, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29620244/egfr-mutations-subset-in-chinese-lung-squamous-cell-carcinoma-patients
#6
Ying Sun, Xin Yin, Miao-Miao Wen, Jiao Zhang, Xue-Jiao Wang, Jing-Hua Xia, Yan-Ning Zhang, Zhi-Pei Zhang, Xiao-Fei Li
Research has identified that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) possess large benefits for adenocarcinoma (ADC), although little benefit for squamous cell carcinoma (SCC). The aim of the present study was to investigate the percentage of patients with SCC with the EGFR mutations subset and the benefits of EGFR TKIs in SCC. In the present study, the EGFR mutations subset was detected with an amplification refractory mutation system in 1,359 clinical SCC tissues. The association of the EGFR mutations subset with clinicopathological parameters was evaluated using the Mann‑Whitney U test, and Kruskal‑Wallis H...
April 5, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29616128/egfr-tki-resistance-and-map17-are-associated-with-cancer-stem-cell-like-properties
#7
Yi Shao, Hui Lv, Dian-Sheng Zhong, Qing-Hua Zhou
Patients with non-small-cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations generally react well to tyrosine kinase inhibitors (TKIs). However acquired resistance eventually occurs. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification and PIK3CA mutation. In recent years, cancer stem cells (CSCs) have been suggested to be involved in TKI resistance. MAP17 is aberrantly overexpressed in a number of malignancies. However, the expression pattern and function of MAP17 in CSCs are still unclear...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29555874/reactivation-of-mutant-egfr-degradation-through-clathrin-inhibition-overcomes-resistance-to-egfr-tyrosine-kinase-inhibitors
#8
Ludovic Ménard, Nicolas Floc'h, Matthew J Martin, Darren Ae Cross
Tyrosine kinase inhibitors (TKIs) targeting mutant-EGFR in NSCLC have been successful to control cancer growth, but acquired resistance inevitably occurs, including mutations directly on EGFR e.g. T790M and C797S. Strategies to prevent such acquired mutations by reducing mutant-EGFR expression have met limited success. Here we propose a new model of mutant-EGFR trafficking and demonstrate that clathrin inhibition induces rapid degradation across a large panel of endogenous mutant-EGFR (Ex19del, L858R, Ex20Ins)...
March 19, 2018: Cancer Research
https://www.readbyqxmd.com/read/29530932/concurrent-alterations-in-egfr-mutant-lung-cancers-associated-with-resistance-to-egfr-kinase-inhibitors-and-characterization-of-mtor-as-a-mediator-of-resistance
#9
Helena Yu, Ken Suzawa, Emmet J Jordan, Ahmet Zehir, Andy Ni, Hyunjae Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria E Arcila, Gregory J Riely, Marc Ladanyi
PURPOSE: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29507487/standardizing-biomarker-testing-for-canadian-patients-with-advanced-lung-cancer
#10
B Melosky, N Blais, P Cheema, C Couture, R Juergens, S Kamel-Reid, M-S Tsao, P Wheatley-Price, Z Xu, D N Ionescu
Background: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor ( EGFR ) inhibitors, is the standard of care in Canada and many parts of the world. Methods: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR , anaplastic lymphoma kinase ( ALK ), ROS1 , BRAF V600 and programmed death-ligand (PD-L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression...
February 2018: Current Oncology
https://www.readbyqxmd.com/read/29506987/investigating-novel-resistance-mechanisms-to-third-generation-egfr-tyrosine-kinase-inhibitor-osimertinib-in-non-small-cell-lung-cancer-patients
#11
Zhe Yang, Nong Yang, Qiuxiang Ou, Yi Xiang, Tao Jiang, Xue Wu, Hua Bao, Xiaoling Tong, Xiaonan Wang, Yang W Shao, Yunpeng Liu, Yan Wang, Caicun Zhou
Background: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown. Methods: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients...
March 5, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29505507/effective-assessment-of-low-times-met-amplification-in-pleural-effusion-after-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-egfr-tkis-acquired-resistance-cases-report
#12
Chang-Guo Wang, Da-Xiong Zeng, Jian-An Huang, Jun-Hong Jiang
RATIONALE: The mechanism of the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) acquired resistance included T790M mutation, cellular-mesenchymal to epithelial transition factor (MET) or EGFR amplification, PIK3CA mutation, and transformation to small cell lung cancer. MET amplification accounted for only about 5% of the resistance cases. PATIENTS CONCERNS: Few report detected MET amplification in pleural effusion. Here, we reported 2 lung adenocarcinoma cases with MET amplification in pleural effusion rapidly responded to crizotinib after EGFR-TKIs acquired resistance...
January 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29483824/dioscin-overcome-tki-resistance-in-egfr-mutated-lung-adenocarcinoma-cells-via-down-regulation-of-tyrosine-phosphatase-shp2-expression
#13
Yao-Chen Wang, De-Wei Wu, Tzu-Chin Wu, Lee Wang, Chih-Yi Chen, Huei Lee
Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29477930/acquired-resistance-to-egfr-targeted-therapy-in-non-small-cell-lung-cancer-mechanisms-and-therapeutic-strategies
#14
REVIEW
Sun Min Lim, Nicholas L Syn, Byoung Chul Cho, Ross A Soo
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...
April 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29467863/detection-of-egfr-and-braf-mutations-by-competitive-allele-specific-taqman-polymerase-chain-reaction-in-lung-adenocarcinoma
#15
Yang Yang, Yi Meng, Hang Zhang, Xiaoyan Shen, Rutian Li, Lixia Yu, Baorui Liu, Lifeng Wang
Epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) expressing sensitive EGFR-mutants. Other drugs target different driver mutants, including the serine/threonine-protein kinase B-raf (BRAF) inhibitor dabrafenib, which has exhibited promising efficacy for treating patients with metastatic BRAF-mutated NSCLC. Therefore, identifying patients carrying mutations that may be treated using targeted therapies is important...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29462254/mechanisms-of-acquired-resistance-to-first-and-second-generation-egfr-tyrosine-kinase-inhibitors
#16
D Westover, J Zugazagoitia, B C Cho, C M Lovly, L Paz-Ares
Patients with non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations within the epidermal growth factor receptor (EGFR) frequently derive significant clinical and radiographic benefits from treatment with EGFR tyrosine kinase inhibitors (TKIs). As such, prospective identification of EGFR mutations is now the standard of care worldwide. However, acquired therapeutic resistance to these agents invariably develops. Over the past 10 years, great strides have been made in defining the molecular mechanisms of EGFR TKI resistance in an effort to design rational strategies to overcome this acquired drug resistance...
January 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29416720/targeting-the-golgi-apparatus-to-overcome-acquired-resistance-of-non-small-cell-lung-cancer-cells-to-egfr-tyrosine-kinase-inhibitors
#17
Yoshimi Ohashi, Mutsumi Okamura, Ryohei Katayama, Siyang Fang, Saki Tsutsui, Akinobu Akatsuka, Mingde Shan, Hyeong-Wook Choi, Naoya Fujita, Kentaro Yoshimatsu, Isamu Shiina, Takao Yamori, Shingo Dan
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...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29411527/heterogeneity-based-multiple-mechanisms-in-the-resistance-to-osimertinib-azd9291-a-case-report
#18
Yutao Liu, Xuezhi Hao, Xingsheng Hu, Junling Li, Yan Wang, Hongyu Wang, Puyuan Xing, Weihua Li, Jianming Ying, Xiaohong Han, Yuankai Shi
Osimertinib is a novel, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor targeting EGFR mutations and the EGFR T790 mutation. Here, we report a woman with EGFR-mutated lung adenocarcinoma who, after 23-month treatment with gefitinib, developed the EGFR T790M mutation, which converted the T790M status from positive to negative before osimertinib treatment and developed MET amplification, leading to rapid progression on osimertinib in two months. Subsequent treatment with crizotinib and c-Met inhibitor plus gefitinib also failed to improve the clinical outcome, suggesting the potential existence of another resistance mechanism...
April 2018: Thoracic Cancer
https://www.readbyqxmd.com/read/29399354/efficacy-of-osimertinib-in-a-patient-with-non-small-cell-lung-cancer-harboring-epithelial-growth-factor-receptor-exon-19-deletion-t790m-mutation-with-poor-performance-status
#19
Yoichi Nishii, Osamu Hataji, Kentaro Ito, Fumiaki Watanabe, Tetsu Kobayashi, Corina D'Alessandro-Gabazza, Masaaki Toda, Osamu Taguchi, Nobuyuki Yamamoto, Esteban C Gabazza
Osimertinib, a third-generation epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated to be effective for treating patients with T790M-positive advanced non-small cell lung cancer (NSCLC) with a relatively good performance status (grade 0-1). Reports of therapeutic response to osimertinib in advanced NSCLC patients with poor performance status are infrequent. The present case report discusses a patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion and T790M mutation with central nervous system involvement and poor performance status...
February 2018: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/29398453/updated-molecular-testing-guideline-for-the-selection-of-lung-cancer-patients-for-treatment-with-targeted-tyrosine-kinase-inhibitors-guideline-from-the-college-of-american-pathologists-the-international-association-for-the-study-of-lung-cancer-and-the-association
#20
Neal I Lindeman, Philip T Cagle, Dara L Aisner, Maria E Arcila, Mary Beth Beasley, Eric H Bernicker, Carol Colasacco, Sanja Dacic, Fred R Hirsch, Keith Kerr, David J Kwiatkowski, Marc Ladanyi, Jan A Nowak, Lynette Sholl, Robyn Temple-Smolkin, Benjamin Solomon, Lesley H Souter, Erik Thunnissen, Ming S Tsao, Christina B Ventura, Murry W Wynes, Yasushi Yatabe
CONTEXT: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update...
March 2018: Journal of Molecular Diagnostics: JMD
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