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https://www.readbyqxmd.com/read/28093244/novel-mutations-on-egfr-leu792-potentially-correlate-to-acquired-resistance-to-osimertinib-in-advanced-nsclc
#1
Kai Chen, Fei Zhou, Wenxiang Shen, Tao Jiang, Xue Wu, Xiaoling Tong, Yang W Shao, Songbing Qin, Caicun Zhou
Osimertinib is an irreversible third generation EGFR tyrosine kinase inhibitor (TKI) and has shown outstanding performances in treating EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) patients, but acquired resistance is inevitable. EGFR C797S is the most notable resistance mechanism to this drug, but other EGFR mutations may also exist. In three lung adenocarcinoma patients resistant to osimertinib, we identified recurrent novel mutations at EGFR Leu792 codon by targeted next generation sequencing (NGS) of cell free DNA (cfDNA) from plasma or pleural effusion...
January 13, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28089942/targeting-egfr-t790m-mutation-in-nsclc-from-biology-to-evaluation-and-treatment
#2
Antonio Passaro, Elena Guerini-Rocco, Alessia Pochesci, Davide Vacirca, Gianluca Spitaleri, Chiara Matilde Catania, Alessandra Rappa, Massimo Barberis, Filippo de Marinis
The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life...
January 12, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28088467/stat3-signaling-mediates-tumour-resistance-to-egfr-targeted-therapeutics
#3
Ahmad A Zulkifli, Fiona H Tan, Tracy L Putoczki, Stanley S Stylli, Rodney B Luwor
Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC)...
January 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28075527/recent-development-of-the-second-and-third-generation-irreversible-egfr-inhibitors
#4
REVIEW
Weiwei Han, Yongli Du
Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non-small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP...
January 11, 2017: Chemistry & Biodiversity
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
#5
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
#6
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/28061461/estimation-of-cell-free-circulating-egfr-mutation-concentration-predicts-outcomes-in-nsclc-patients-treated-with-egfr-tkis
#7
Yan-Juan Zhu, Hai-Bo Zhang, Yi-Hong Liu, Fu-Li Zhang, Ya-Zhen Zhu, Yong Li, Jian-Ping Bai, Li-Rong Liu, Yan-Chun Qu, Xin Qu, Xian Chen, Yan Li, Guang-Juan Zheng
Detection of circulating tumor DNA using droplet digital polymerase chain reaction (ddPCR) is a highly-sensitive, minimally invasive alternative to serial biopsies for assessment and management of cancer. We used ddPCR to assess the utility of measuring plasma concentrations of common epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, and T790M) in 57 non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). High baseline plasma EGFR mutation (pEGFRmut) concentrations were associated with shorter progression-free survival (8...
January 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28033579/a-structure-guided-optimization-of-pyrido-2-3-d-pyrimidin-7-ones-as-selective-inhibitors-of-egfr-l858r-t790m-mutant-with-improved-pharmacokinetic-properties
#8
Lei Yu, Minhao Huang, Tianfeng Xu, Linjiang Tong, Xiao-E Yan, Zhang Zhang, Yong Xu, Caihong Yun, Hua Xie, Ke Ding, Xiaoyun Lu
Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR(T790M) inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR(L858R/T790M) kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%...
December 3, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28031840/concomitant-t790m-mutation-and-small-cell-lung-cancer-transformation-after-acquired-resistance-to-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor
#9
Kohei Fujita, Young Hak Kim, Akihiko Yoshizawa, Tadashi Mio, Michiaki Mishima
A 70-year-old man was admitted to our hospital with an abnormal chest X-ray shadow. Bronchoscopy revealed an adenocarcinoma tumour with an epidermal growth factor receptor (EGFR) exon 19 deletion. Positron emission tomography-computed tomography scanning and magnetic resonance imaging showed advanced stage IV lung cancer. He was treated with erlotinib as a first-line drug, which maintained a clinical response for 16 months. After disease progression, a re-biopsy was done from the tumour in the right lower lobe...
January 2017: Respirology Case Reports
https://www.readbyqxmd.com/read/28031832/effectiveness-of-afatinib-in-lung-cancer-with-paralytic-ileus-due-to-peritoneal-carcinomatosis
#10
Haruki Kobayashi, Kazushige Wakuda, Toshiaki Takahashi
A 61-year-old never-smoking woman with stage IV lung adenocarcinoma with initially unknown epidermal growth factor receptor (EGFR) status, lung metastasis, pleural dissemination, and malignant pleural effusion in 2007 received 10 prior anti-cancer regimens including gefitinib as second- and ninth-line treatments, with minimal efficacy with gefitinib. EGFR mutation analysis performed in pleural effusion specimens during ninth-line gefitinib was negative. In 2015, she developed progressive disease with peritoneal dissemination...
November 2016: Respirology Case Reports
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
#11
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/28002980/targeting-the-egfr-t790m-mutation-in-non-small-cell-lung-cancer
#12
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
#13
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/27999211/the-role-of-t790m-mutation-in-egfr-tki-re-challenge-for-patients-with-egfr-mutant-advanced-lung-adenocarcinoma
#14
Qiuyi Zhang, Ee Ke, Feiyu Niu, Wei Deng, Zhihong Chen, Chongrui Xu, Xuchao Zhang, Ning Zhao, Jian Su, Jinji Yang, Honghong Yan, Yilong Wu, Qing Zhou
Epidermal growth factor receptor (EGFR) T790M mutation has shown to be associated with the clinical outcomes of patients after initial EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy in EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, its predictive role in EGFR-TKI re-challenge remains unknown. The present study was aimed to explore the correlation between T790M mutation and any benefits from EGFR-TKI re-challenge. We retrospectively reviewed 922 consecutive patients with EGFR-mutant non-small cell lung cancer (NSCLC) patients administered with gefitinib/erlotinib at Guangdong General Hospital...
December 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27994736/discovery-of-novel-bruton-s-tyrosine-kinase-btk-inhibitors-bearing-a-n-9-diphenyl-9h-purin-2-amine-scaffold
#15
Yang Ge, Yue Jin, Changyuan Wang, Jianbin Zhang, Zeyao Tang, Jinyong Peng, Kexin Liu, Yanxia Li, Youwen Zhou, Xiaodong Ma
Based on the pyrimidine skeleton of EGFR(T790M) inhibitors, a series of N,9-diphenyl-9H-purin-2-amine derivatives were identified as effective BTK inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC50 values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of BTK with concentrations of 7.75 and 12.6 μM...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27990348/three-color-crystal-digital-pcr
#16
J Madic, A Zocevic, V Senlis, E Fradet, B Andre, S Muller, R Dangla, M E Droniou
Digital PCR is an exciting new field for molecular analysis, allowing unprecedented precision in the quantification of nucleic acids, as well as the fine discrimination of rare molecular events in complex samples. We here present a novel technology for digital PCR, Crystal Digital PCR™, which relies on the use of a single chip to partition samples into 2D droplet arrays, which are then subjected to thermal cycling and finally read using a three-color fluorescence scanning device. This novel technology thus allows three-color multiplexing, which entails a different approach to data analysis...
December 2016: Biomolecular Detection and Quantification
https://www.readbyqxmd.com/read/27989430/osimertinib-effective-in-egfr-t790m-positive-lung-cancer
#17
Susan Mayor
No abstract text is available yet for this article.
January 2017: Lancet Oncology
https://www.readbyqxmd.com/read/27986747/histone-deacetylase-3-inhibition-overcomes-bim-deletion-polymorphism-mediated-osimertinib-resistance-in-egfr-mutant-lung-cancer
#18
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
#19
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/27969496/ps01-28-epithelial-mesenchymal-transition-in-tki%C3%A2-resistant-nsclc-with-t790m-mutation-topic-medical-oncology
#20
Tsatsral Iderzorig, Gagan Chhabra, Neelu Puri
No abstract text is available yet for this article.
November 2016: Journal of Thoracic Oncology
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