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https://www.readbyqxmd.com/read/28642172/egfr-t790m-ctdna-testing-platforms-and-their-role-as-companion-diagnostics-correlation-with-clinical-outcomes-to-egfr-tkis
#1
Zhiyong Liang, Ying Cheng, Yuan Chen, Yanping Hu, Wei-Ping Liu, You Lu, Jie Wang, Ye Wang, Gang Wu, Jian-Ming Ying, He-Long Zhang, Xu-Chao Zhang, Yi-Long Wu
Somatic mutation in the epidermal growth factor receptor (EGFR) predict clinical response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and is a promising target for personalised medicine. EGFR mutations have prognostic value. Initially patients respond well to tyrosine kinase inhibitors but finally they would develop resistance and about 50% of this resistance can be attributed to the emergence of EGFR resistant mutation, T790M. This necessitates the need for genetic testing for clinical management of patients...
June 19, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28635227/-mechanism-and-clinical-efficacy-of-third-generation-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-in-non-small-cell-lung-cancer
#2
X X Chen, C C Zhou
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, most of patients will develop resistance to TKIs treatment due to the emergence of the T790M mutation. The third-generation EGFR-TKI is highly selective and efficient for activating mutants (EGFR sensitive mutations) and resistance mutant (T790M+ ). This review summarizes the mechanism and clinical efficacy of the third-generation EGFR-TKI in NSCLC patients...
June 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28630494/structure-guided-design-of-c4-alkyl-1-4-dihydro-2h-pyrimido-4-5-d-1-3-oxazin-2-ones-as-potent-and-mutant-selective-epidermal-growth-factor-receptor-egfr-l858r-t790m-inhibitors
#3
Yongjia Hao, Jiankun Lyu, Rong Qu, Deheng Sun, Zhenjiang Zhao, Zhuo Chen, Jian Ding, Hua Xie, Yufang Xu, Honglin Li
Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR(L858R/T790M) (H1975 cell lines) over EGFR(WT) (A431 cell lines)...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28625653/most-t790m-mutations-are-present-on-the-same-egfr-allele-as-activating-mutations-in-patients-with-non-small-cell-lung-cancer
#4
Noriko Hidaka, Eiji Iwama, Naoki Kubo, Taishi Harada, Kohta Miyawaki, Kentaro Tanaka, Isamu Okamoto, Eishi Baba, Koichi Akashi, Hiroyuki Sasaki, Yoichi Nakanishi
OBJECTIVES: The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625643/sequential-liquid-biopsies-reveal-dynamic-alterations-of-egfr-driver-mutations-and-indicate-egfr-amplification-as-a-new-mechanism-of-resistance-to-osimertinib-in-nsclc
#5
Franciele H Knebel, Fabiana Bettoni, Andrea K Shimada, Manoel Cruz, João Victor Alessi, Marcelo V Negrão, Luiz Fernando L Reis, Artur Katz, Anamaria A Camargo
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...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625641/emergence-of-novel-and-dominant-acquired-egfr-solvent-front-mutations-at-gly796-g796s-r-together-with-c797s-r-and-l792f-h-mutations-in-one-egfr-l858r-t790m-nsclc-patient-who-progressed-on-osimertinib
#6
Sai-Hong Ignatius Ou, Jean Cui, Alexa B Schrock, Michael E Goldberg, Viola W Zhu, Lee Albacker, Philip J Stephens, Vincent A Miller, Siraj M Ali
Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib...
June 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28625519/multiplex-ultrasensitive-genotyping-of-patients-with-non-small-cell-lung-cancer-for-epidermal-growth-factor-receptor-egfr-mutations-by-means-of-picodroplet-digital-pcr
#7
Masaru Watanabe, Tomoya Kawaguchi, Shun-Ichi Isa, Masahiko Ando, Akihiro Tamiya, Akihito Kubo, Hideo Saka, Sadanori Takeo, Hirofumi Adachi, Tsutomu Tagawa, Osamu Kawashima, Motohiro Yamashita, Kazuhiko Kataoka, Yukito Ichinose, Yukiyasu Takeuchi, Katsuya Watanabe, Akihide Matsumura, Yasuhiro Koh
Epidermal growth factor receptor (EGFR) mutations have been used as the strongest predictor of effectiveness of treatment with EGFR tyrosine kinase inhibitors (TKIs). Three most common EGFR mutations (L858R, exon 19 deletion, and T790M) are known to be major selection markers for EGFR-TKIs therapy. Here, we developed a multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction. Serial-dilution experiments with genomic DNA harboring EGFR mutations revealed linear performance, with analytical sensitivity ~0...
June 7, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28624467/comprehensive-analysis-of-egfr-mutant-abundance-and-its-effect-on-efficacy-of-egfr-tkis-in-advanced-nsclc-with-egfr-mutations
#8
Xuefei Li, Weijing Cai, Guohua Yang, Chunxia Su, Shengxiang Ren, Chao Zhao, Rongjun Hu, Xiaoxia Chen, Guanghui Gao, Zhiwei Guo, Wei Li, Caicun Zhou, Fred R Hirsch
BACKGROUND: It is not enough sensitive to use a qualitative detection method with sensitivity of 1% to determine EGFR status in advanced NSCLC and guide precise therapy in clinical practice. OBJECTIVE: To explore the relationship between the abundance of EGFR mutations and efficacy of EGFR-TKIs. METHODS: We used ARMS plus (ARMS+) to quantitatively evaluate the abundance of EGFR mutations in 201 advanced NSCLC patients. A cut-off value of the abundance of EGFR mutations was determined by ROC analysis in training group and was validated in validation group...
June 14, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28623122/a-randomized-phase-ii-study-comparing-nivolumab-with-carboplatin-pemetrexed-for-patients-with-egfr-mutation-positive-nonsquamous-non-small-cell-lung-cancer-who-acquire-resistance-to-tyrosine-kinase-inhibitors-not-due-to-a-secondary-t790m-mutation-rationale
#9
Hidetoshi Hayashi, Yasutaka Chiba, Kazuko Sakai, Tomonobu Fujita, Hiroshige Yoshioka, Daisuke Sakai, Chiyoe Kitagawa, Tateaki Naito, Koji Takeda, Isamu Okamoto, Tetsuya Mitsudomi, Yutaka Kawakami, Kazuto Nishio, Shinichiro Nakamura, Nobuyuki Yamamoto, Kazuhiko Nakagawa
Antibodies to programmed cell death-1 (PD-1), such as nivolumab, have shown promising clinical activity in patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy appears to be less pronounced in patients with such tumors harboring epidermal growth factor receptor gene (EGFR) mutations. Recent findings suggest that patients with EGFR mutation-positive NSCLC who develop resistance to tyrosine kinase inhibitors (TKIs) due to mechanisms other than acquisition of the secondary T790M mutation of EGFR are more likely to benefit from nivolumab treatment, possibly as a result of a higher level of expression of the PD-1 ligand PD-L1, than are patients who are T790M-positive...
May 25, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28620690/acquired-resistance-to-erlotinib-in-egfr-mutation-positive-lung-adenocarcinoma-among-hispanics-clicap
#10
Andrés F Cardona, Oscar Arrieta, Martín Ignacio Zapata, Leonardo Rojas, Beatriz Wills, Noemí Reguart, Niki Karachaliou, Hernán Carranza, Carlos Vargas, Jorge Otero, Pilar Archila, Claudio Martín, Luis Corrales, Mauricio Cuello, Carlos Ortiz, Luis E Pino, Rafael Rosell, Zyanya Lucia Zatarain-Barrón
BACKGROUND: Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. OBJECTIVE: The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. PATIENTS AND METHODS: EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015...
June 15, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28620581/third-generation-tyrosine-kinase-inhibitors-targeting-epidermal-growth-factor-receptor-mutations-in-non-small-cell-lung-cancer
#11
REVIEW
Tristan A Barnes, Grainne M O'Kane, Mark David Vincent, Natasha B Leighl
Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28616379/re-biopsy-after-relapse-of-targeted-therapy-t790m-after-epidermal-growth-factor-mutation-where-and-why-based-on-a-case-series
#12
Paul Zarogoulidis, Aggeliki Rapti, Chrysanthi Sardeli, Panagiotis Chinelis, Anastasia Athanasiadou, Katerina Paraskevaidou, Anastasios Kallianos, Lemonia Veletza, Georgia Trakada, Wolfgang Hohenforst-Schmidt, Haidong Huang
Guidelines for the treatment of non-small cell lung cancer adenocarcinoma positive in epidermal growth factor mutations indicate tyrosine kinase inhibitors. There are currently three tyrosine kinase inhibitors that can be used as first line treatment: gefitinib, erlotinib and afatinib. Regarding erlotinib and afatinib dosage can be modified in the case of severe adverse effects. In the case of disease relapse investigation for T790M mutation has to be made either with re-biopsy or liquid biopsy and osimertinib has to be administered when T790M is diagnosed...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28607578/osimertinib-in-patients-with-advanced-epidermal-growth-factor-receptor-t790m-mutation-positive-non-small-cell-lung-cancer-rationale-evidence-and-place-in-therapy
#13
REVIEW
Biagio Ricciuti, Sara Baglivo, Luca Paglialunga, Andrea De Giglio, Guido Bellezza, Rita Chiari, Lucio Crinò, Giulio Metro
The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit...
June 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28606923/detection-of-driver-and-resistance-mutations-in-leptomeningeal-metastases-of-nsclc-by-next-generation-sequencing-of-cerebrospinal-fluid-circulating-tumor-cells
#14
Ben-Yuan Jiang, Yang-Si Li, Wei-Bang Guo, Xu-Chao Zhang, Zhihong Chen, Jian Su, Wenzhao Zhong, Xue-Ning Yang, Jinji Yang, Yang W Shao, Biao Huang, Yan-Hui Liu, Qing Zhou, Hai-Yan Tu, Hua-Jun Chen, Zhen Wang, Chongrui Xu, Bin-Chao Wang, Shu-Yu Wu, Cun-Yi Gao, Xian Zhang, Yi-Long Wu
<p>Leptomeningeal metastases (LM) are more common in non-small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of LM.</p> <br />Experimental Design: <p>We compared the CellSearch Assay™, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected LM. Next-Generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTCs) of 19 patients...
June 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28603991/trisubstituted-pyridinylimidazoles-as-potent-inhibitors-of-the-clinically-resistant-l858r-t790m-c797s-egfr-mutant-targeting-of-both-hydrophobic-regions-and-the-phosphate-binding-site
#15
Marcel Günther, Jonas Lategahn, Michael Juchum, Eva Döring, Marina Keul, Julian Engel, Hannah L Tumbrink, Daniel Rauh, Stefan Laufer
Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28599456/dynamic-monitoring-of-egfr-mutations-in-circulating-cell-free-dna-for-egfr-mutant-metastatic-patients-with-lung-cancer-early-detection-of-drug-resistance-and-prognostic-significance
#16
Jianjiao Ni, Linqian Weng, Yi Liu, Zhao Sun, Chunmei Bai, Yingyi Wang
Detecting genetic mutations in circulating cell-free DNA (cfDNA) is a promising approach of liquid biopsy. Between June 2014 and May 2015, 168 plasma samples were collected monthly from 20 patients with metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation receiving gefitinib therapy. Clinically relevant EGFR mutations, including exon 19 deletion, L858R and T790M, were quantified using droplet digital polymerase chain reaction. In baseline samples, 19 (95.0%) patients had the same mutation with the matched tumors, and pretreatment T790M mutations were also detected in 3 (15...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28599309/marsdenia-tenacissima-extract-overcomes-axl-and-met-mediated-erlotinib-and-gefitinib-cross-resistance-in-non-small-cell-lung-cancer-cells
#17
Shu-Yan Han, Wei Zhao, Hai-Bo Han, Hong Sun, Dong Xue, Yan-Na Jiao, Xi-Ran He, Shan-Tong Jiang, Ping-Ping Li
Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28596108/association-between-egfr-t790m-status-and-progression-patterns-during-initial-egfr-tki-treatment-in-patients-harboring-egfr-mutation
#18
Yuko Oya, Tatsuya Yoshida, Hiroaki Kuroda, Junichi Shimizu, Yoshitsugu Horio, Yukinori Sakao, Yoshitaka Inaba, Toyoaki Hida, Yasushi Yatabe
BACKGROUND: Emergence of the T790M point mutation in exon 20 of the epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of this study was to investigate the association between T790M mutation status and the progression patterns during EGFR-TKI treatment. METHODS: We reviewed 181 patients with advanced non-small-cell lung cancer harboring EGFR mutation, who were evaluated for T790M mutation status after initial EGFR-TKI failure (gefitinib, erlotinib, or afatinib)...
May 10, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28591715/brca2-egfr-and-ntrk-mutations-in-mismatch-repair-deficient-colorectal-cancers-with-msh2-or-mlh1-mutations
#19
Safoora Deihimi, Avital Lev, Michael Slifker, Elena Shagisultanova, Qifang Xu, Kyungsuk Jung, Namrata Vijayvergia, Eric A Ross, Joanne Xiu, Jeffrey Swensen, Zoran Gatalica, Mark Andrake, Roland L Dunbrack, Wafik S El-Deiry
Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28588734/plasma-t790m-and-hgf-as-potential-predictive-markers-for-egfr-tki-re-challenge
#20
Tomomi Nakamura, Naomi Watanabe, Akemi Sato, Kazutoshi Komiya, Hitomi Umeguchi, Toshiya Hosomi, Mitsuharu Hirai, Eisaburo Sueoka, Shinya Kimura, Naoko Sueoka-Aragane
Re-challenge with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has been suggested to potentially improve survival in certain populations of patients with advanced lung cancer, but predictive markers for the success of EGFR-TKI re-challenge have not been identified. The present study analyzed 16 re-challenges with EGFR-TKI undertaken in 12 patients with lung adenocarcinoma by investigating T790M and hepatocyte growth factor (HGF) in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe system...
June 2017: Oncology Letters
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