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https://www.readbyqxmd.com/read/29780256/the-utilization-of-next-generation-sequencing-to-detect-somatic-mutations-and-predict-clinical-prognosis-of-chinese-non-small-cell-lung-cancer-patients
#1
Liming Cao, Long Long, Min Li, Huaping Yang, Pengbo Deng, Xinru Mao, Jianxing Xiang, Bing Li, Tengfei Zhang, Chengping Hu
Purpose: The development of next-generation sequencing (NGS) has revolutionized the understanding of oncogenesis of multiple types of cancer, including non-small cell lung cancer (NSCLC). However, there has been some debate over the utility of NGS for predicting patient prognosis and determining molecular targeted therapy. Therefore, we sought to demonstrate the numerous applications of NGS in the prognostic predictions and treatment of NSCLC patients. Materials and methods: We performed NGS on either liquid or tissue tumor biopsies obtained from 53 NSCLC patients...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29775809/transient-asymptomatic-pulmonary-opacities-during-osimertinib-treatment-and-its-clinical-implication
#2
Hansang Lee, Ho Yun Lee, Jong-Mu Sun, Se-Hoon Lee, Youjin Kim, Song Ee Park, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
INTRODUCTION: Osimertinib is an oral, potent, irreversible 3rd generation EGFR tyrosine kinase inhibitor (TKI) approved for the treatment of T790M positive non-small cell lung cancer (NSCLC) patients who failed 1st or 2nd generation EGFR TKIs. Interstitial lung disease (ILD) is a rare complication with osimertinib, occurring in 1-3%. Recently, relatively high incidence of transient asymptomatic pulmonary opacities (TAPOs) which are different from ILD has been described. However, its clinical implication has not been fully determined yet...
May 15, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29766737/identification-of-small-molecule-egfr-allosteric-inhibitors-by-high-throughput-docking
#3
Fabiana Caporuscio, Annachiara Tinivella, Valentina Restelli, Marta S Semrau, Luca Pinzi, Paola Storici, Massimo Broggini, Giulio Rastelli
AIM: The EGFR inhibitors represent the first-line treatment of non-small-cell lung cancer. However, the emergence of resistance urgently requires the development of new inhibitors targeting drug-resistant mutants. METHODOLOGY: A recently released structure of an EGFR kinase domain in complex with an allosteric inhibitor and a mutant protein model derived from it were used to set up a low-cost high-throughput docking protocol for the fast identification of EGFR allosteric inhibitors...
May 16, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29764589/-influence-of-different-therapies-on-egfr-mutants-by-circulating-cell-free-dna-of-lung-adenocarcinoma-and-prognosis
#4
Fei Su, Ke Zheng, Yiyun Fu, Qian Wu, Yuan Tang, Weiya Wang, Lili Jiang
BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutation is closely related to the EGFR-TKI target treatment and prognosis of lung adenocarcinoma patients. The mutation status of EGFR is limited by tissue detection. The purpose of this study was to investigate the difference of EGFR mutants in plasmacirculating cell-free DNA (cfDNA) obtained from patients with non-small cell lung cancer (NSCLC) in three groups: pre-therapy, after traditional chemotherapy and targeted therapy...
May 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/29764505/xenograft-tumors-derived-from-malignant-pleural-effusion-of-the-patients-with-non-small-cell-lung-cancer-as-models-to-explore-drug-resistance
#5
Yunhua Xu, Feifei Zhang, Xiaoqing Pan, Guan Wang, Lei Zhu, Jie Zhang, Danyi Wen, Shun Lu
BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively...
May 9, 2018: Cancer communications
https://www.readbyqxmd.com/read/29761660/feasibility-of-re-biopsy-and-egfr-mutation-analysis-in-patients-with-non-small-cell-lung-cancer
#6
Tae-Ok Kim, In-Jae Oh, Bo Gun Kho, Ha Young Park, Jin Sun Chang, Cheol-Kyu Park, Hong-Joon Shin, Jung-Hwan Lim, Yong-Soo Kwon, Yu-Il Kim, Sung-Chul Lim, Young-Chul Kim, Yoo-Duk Choi
BACKGROUND: In cases of EGFR-tyrosine kinase inhibitor (TKI) failure, re-biopsy may be useful to understand resistance mechanisms and guide further treatment decisions. However, performing re-biopsy is challenging because of several hurdles. We assessed the feasibility of re-biopsy in advanced non-small cell lung cancer (NSCLC) patients in real-world clinical practice. METHODS: We retrospectively reviewed the clinical and pathologic data of advanced NSCLC patients who experienced disease progression after previous treatment with EGFR-TKIs at a single tertiary hospital in Korea between January 2014 and December 2016...
May 14, 2018: Thoracic Cancer
https://www.readbyqxmd.com/read/29760807/quality-control-of-next-generation-sequencing-based-in-vitro-diagnostic-test-for-onco-relevant-mutations-using-multiplex-reference-materials-in-plasma
#7
Donglai Liu, Haiwei Zhou, Dawei Shi, Shu Shen, Yabin Tian, Lin Wang, Jiatao Lou, Rong Cong, Juan Lu, Henghui Zhang, Meiru Zhao, Shida Zhu, Zhisheng Cao, Ruilin Jin, Yin Wang, Xiaoni Zhang, Guohua Yang, Youchun Wang, Chuntao Zhang
Background: Widespread clinical implementation of next-generation sequencing (NGS)-based cancer in vitro diagnostic tests (IVDs) highlighted the urgency to establish reference materials which could provide full control of the process from nucleic acid extraction to test report generation. The formalin-fixed, paraffin-embedded (FFPE) tissue and blood plasma containing circulating tumor deoxyribonucleic acid (ctDNA) were mostly used for clinically detecting onco-relevant mutations. Methods: We respectively developed multiplex FFPE and plasma reference materials covering three clinically onco-relevant mutations within the epidermal growth factor receptor ( EGFR ) gene at serial allelic frequencies...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29758406/molecular-dynamics-guided-development-of-indole-based-dual-inhibitors-of-egfr-t790m-and-c-met
#8
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/29755953/first-line-treatment-in-egfr-mutant-non-small-cell-lung-cancer-is-there-a-best-option
#9
REVIEW
Ajaz Bulbul, Hatim Husain
First generation or second generation EGFR tyrosine kinase inhibitors are currently the standard of care for the first-line management of non-small cell lung cancer (NSCLC) patients with activating mutations within the kinase domain of the epidermal growth factor receptor gene (1, 2). Resistance to targeted therapy can develop after 9-11 months (3-8). Third generation inhibitors were developed to target the EGFR T790M clone, which is the most common dominant second site resistance mutation after first or second generation inhibitors...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29754184/discovery-of-a-potent-and-mutant-selective-egfr-inhibitor-that-overcomes-t790m-mediated-resistance-in-lung-cancer
#10
Dong Ha Kim, Yun Jung Choi, Seon Ye Kim, Jung-Eun Lee, Ki Jung Sung, Young Hoon Sung, Woo Sung Kim, Sung-Eun Kim, Hyung Chul Ryu, Jae Sun Kim, Lu Guangying, Chang-Min Choi, Jin Kyung Rho, Jae Cheol Lee
BACKGROUND: Despite remarkable activity in epidermal growth factor receptor (EGFR)-mutant lung cancer patients, the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) is limited by the emergence of acquired resistance, which is mostly caused by a secondary T790M mutation. Fortunately, newly developed, mutant-selective EGFR-TKIs against T790M have been proven as an effective therapeutic approach although only osimertinib has received the FDA approval until now. OBJECTIVE: To determine the in vitro and in vivo efficacy of a new EGFR TKI, OBX1-012 in cells with mutant EGFR...
May 12, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29751135/brief-report-on-the-detection-of-the-egfr-t790m-mutation-in-exhaled-breath-condensate-from-lung-cancer-patients
#11
Robert J Smyth, Sinead M Toomey, Alexander Sartori, Emer O Hanrahan, Sinead D Cuffe, Oscar S Breathnach, Ross K Morgan, Bryan T Hennessy
The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in non-small cell lung cancer. Patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Unfortunately the low sensitivity of plasma for T790M detection has limited its clinical use. Exhaled breath condensate (EBC) is an easily collected sample, known to harbour cfDNA, including lung cancer mutations...
May 8, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29732058/l718q-mutant-egfr-escapes-covalent-inhibition-by-stabilizing-a-non-reactive-conformation-of-the-lung-cancer-drug-osimertinib
#12
D Callegari, K E Ranaghan, C J Woods, R Minari, M Tiseo, M Mor, A J Mulholland, A Lodola
Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step ( i...
March 14, 2018: Chemical Science
https://www.readbyqxmd.com/read/29730192/discovery-of-novel-2-4-diarylaminopyrimidine-derivatives-as-potent-and-selective-epidermal-growth-factor-receptor-egfr-inhibitors-against-l858r-t790m-resistance-mutation
#13
Qi Yan, Yuzhe Chen, Baiyou Tang, Qiang Xiao, Rong Qu, Linjiang Tong, Jian Liu, Jian Ding, Yi Chen, Ning Ding, Wenfu Tan, Hua Xie, Yingxia Li
A series of novel 2,4-diarylaminopyrimidine derivatives of AZD9291 were discovered as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. The majority of these compounds exhibited moderate to excellent EGFR T790 M/L858R inhibitory activities and comparable anti-proliferative activities against double mutant over-expressed NCI-H1975 cells to that of AZD9291. The most promising compounds 8a displayed an IC50 of 4.1 nM against EGFR L858R/T790M mutants. 8a also showed excellent cytotoxic effect against NCI-H1975 cells with an IC50 of 59 nM and 100-fold selectivity over wide-type EGFR over-expressed A431 cells...
April 27, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29721209/radiotherapy-increases-plasma-levels-of-tumoral-cell-free-dna-in-non-small-cell-lung-cancer-patients
#14
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/29720878/-egfr-kras-braf-pten-and-pik3ca-mutation-in-plasma-of-small-cell-lung-cancer-patients
#15
Hong-Yang Lu, Jing Qin, Na Han, Lei Lei, Fajun Xie, Chenghui Li
Background: Small cell lung cancer (SCLC) is an aggressive and deadly neuroendocrine tumor derived from bronchial epithelial cells. Although it results in a 95% mortality rate, the development of targeted therapies for SCLCs has lagged behind. The aim of this study is to better research mutation characteristics of SCLC and identify potential biomarkers for target therapy. Methods: We utilized high-resolution melting analysis to identify the mutations in epidermal growth factor receptor ( EGFR ), Kirsten rat sarcoma viral oncogene ( KRAS ), v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ), phosphatase and tensin homolog ( PTEN ), and phosphatidylinositol-3-kinase catalytic ( PIK3CA ) from the blood...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29719623/validation-and-comparison-of-two-ngs-assays-for-the-detection-of-egfr-t790m-resistance-mutation-in-liquid-biopsies-of-nsclc-patients
#16
Claudia Vollbrecht, Annika Lehmann, Dido Lenze, Michael Hummel
Analysis of circulating cell-free DNA (cfDNA) derived from peripheral blood ("liquid biopsy") is an attractive alternative to identify non-small cell lung cancer (NSCLC) patients with the EGFR T790M mutation eligible for 3rd generation tyrosine kinase inhibitor therapy. We evaluated two PCR-based next generation sequencing (NGS) approaches, one including unique molecular identifiers (UMI), with focus on highly sensitive EGFR T790M mutation detection. Therefore, we extracted and sequenced cfDNA from synthetic plasma samples spiked with mutated DNA at decreasing allele frequencies and from 21 diagnostic NSCLC patients...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29719432/evidence-based-best-practices-for-egfr-t790m-testing-in-lung-cancer-in-canada
#17
T Stockley, C A Souza, P K Cheema, B Melosky, S Kamel-Reid, M S Tsao, A Spatz, A Karsan
Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as first-line systemic therapy for patients with non-small-cell lung cancer (nsclc) having mutations in the EGFR gene. Resistance to tkis eventually occurs in all nsclc patients treated with such drugs. In patients with resistance to tkis caused by the EGFR T790M mutation, the third-generation tki osimertinib is now the standard of care. For optimal patient management, accurate EGFR T790M testing is required. A multidisciplinary working group of pathologists, laboratory medicine specialists, medical oncologists, a respirologist, and a thoracic radiologist from across Canada was convened to discuss best practices for EGFR T790M mutation testing in Canada...
April 2018: Current Oncology
https://www.readbyqxmd.com/read/29715155/acquired-egfr-t790m-mutation-after-relapse-following-egfr-tki-therapy-a-population-based-multi-institutional-study
#18
MULTICENTER STUDY
Takayuki Kaburagi, Moriyuki Kiyoshima, Takeshi Nawa, Hideo Ichimura, Takefumi Saito, Kenji Hayashihara, Hideyasu Yamada, Hiroaki Satoh, Takeo Endo, Yoshihisa Inage, Kazuhito Saito, Masaharu Inagaki, Nobuyuki Hizawa, Yukio Sato, Hiroichi Ishikawa, Mitsuaki Sakai, Koichi Kamiyama, Norihiro Kikuchi, Hiroyuki Nakamura, Kinya Furukawa, Takahide Kodama, Takaaki Yamashita, Akihiro Nomura, Susumu Yoshida
AIM: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting. MATERIALS AND METHODS: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people. RESULTS: We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42...
May 2018: Anticancer Research
https://www.readbyqxmd.com/read/29713646/mutational-profiling-of-non-small-cell-lung-cancer-resistant-to-osimertinib-using-next-generation-sequencing-in-chinese-patients
#19
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/29707292/selective-gene-amplification-to-detect-the-t790m-mutation-in-plasma-from-patients-with-advanced-non-small-cell-lung-cancer-nsclc-who-have-developed-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-egfr-tki-resistance
#20
Shingo Nishikawa, Hideharu Kimura, Hayato Koba, Taro Yoneda, Satoshi Watanabe, Tamami Sakai, Johsuke Hara, Takashi Sone, Kazuo Kasahara, Shinji Nakao
Background: The epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, tissues for the genotyping of the EGFR T790M mutation can be difficult to obtain in a clinical setting. The aims of this study were to evaluate a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients using the PointMan™ EGFR DNA enrichment kit, which is a novel method for the selective amplification of specific genotype sequences...
March 2018: Journal of Thoracic Disease
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