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https://www.readbyqxmd.com/read/28333951/prognostic-value-of-plasma-egfr-ctdna-in-nsclc-patients-treated-with-egfr-tkis
#1
Chengjuan Zhang, Bing Wei, Peng Li, Ke Yang, Zhizhong Wang, Jie Ma, Yongjun Guo
OBJECTIVE: Epidermal growth factor receptor (EGFR) specific mutations have been known to improve survival of patients with non-small-cell lung carcinoma (NSCLC). However, whether there are any changes of EGFR mutations after targeted therapy and its clinical significance is unclear. This study was to identify the status of EGFR mutations after targeted therapy and predict the prognostic significance for NSCLC patients. METHODS: A total of forty-five (45) NSCLC patients who received EGFR-TKI therapy were enrolled...
2017: PloS One
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#2
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28331001/quantitative-tyrosine-phosphoproteomics-of-egfr-tyrosine-kinase-inhibitor-treated-lung-adenocarcinoma-cells-reveals-potential-novel-biomarkers-of-therapeutic-response
#3
Xu Zhang, Tapan Maity, Manoj K Kashyap, Mukesh Bansal, Abhilash Venugopalan, Sahib Singh, Shivangi Awasthi, Arivusudar Marimuthu, Harrys Kishore Charles Jacob, Natalya Belkina, Stephanie Pitts, Constance M Cultraro, Shaojian Gao, Fatos Kirkali, Romi Biswas, Raghothama Chaerkady, Andrea Califano, Akhilesh Pandey, Udayan Guha
Mutations in the Epidermal growth factor receptor (EGFR) kinase domain, such as the L858R missense mutation and deletions spanning the conserved sequence 747LREA750, are sensitive to tyrosine kinase inhibitors (TKIs). The gatekeeper site residue mutation, T790M accounts for around 60% of acquired resistance to EGFR TKIs. The first generation EGFR TKIs, erlotinib and gefitinib, and the second generation inhibitor, afatinib are FDA approved for initial treatment of EGFR mutated lung adenocarcinoma. The predominant biomarker of EGFR TKI responsiveness is the presence of EGFR TKI-sensitizing mutations...
March 22, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28302223/-current-status-and-prospect-of-t790m-mutation-in-non-small-cell-lung-cancer
#4
Qin Yu, Da Jiang, Ying Li
Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) is regarded as the main accepted first-line treatment on EGFR mutation in non-small cell lung cancer (NSCLC). Although targeted therapy for the first and two generation of TKIs may lead to longer progression-free survival (PFS) and better tolerance for patients, the long-term treatment will inevitably lead to drug resistance. Among them, more than 50% of acquired resistance is associated with T790M mutation. The latest guidelines from the National Comprehensive Cancer Network (NCCN) have been proposed that the three generation of TKI (Osimertinib) can be used in first-line TKI therapy progress with detecting T790M mutations in patients...
March 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28296233/sustained-response-to-standard-dose-osimertinib-in-a-patient-with-plasma-t790m-positive-leptomeningeal-metastases-from-primary-lung-adenocarcinoma
#5
Oscar Siu-Hong Chan, Warren Kam-Wing Leung, Rebecca Mei-Wan Yeung
A 44-year-old male, never smoker, suffers from stage IV adenocarcinoma of the right lung with epidermal growth factor receptor (EGFR) exon-21 L858R point mutation on initial presentation. After 23 months of treatment with gefitinib, intercalated with multiple courses of radiotherapy, leptomeningeal metastases (LMs) developed. Acquired T790M mutation was confirmed by the droplet digital polymerase chain reaction plasma EGFR test. After switching to osimertinib at the standard dose, his neurocognitive function improved clinically, coupled with sustained radiological improvement...
March 15, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28290719/molecular-dynamics-and-pharmacophore-modelling-studies-of-different-subtype-alk-and-egfr-t790m-inhibitors-in-nsclc
#6
P K Singh, O Silakari
Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r(2) = 0.96, q(2) = 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r(2) = 0.92, q(2) = 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M)...
March 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28289161/distinct-afatinib-resistance-mechanisms-identified-in-lung-adenocarcinoma-harboring-an-egfr-mutation
#7
Toshimitsu Yamaoka, Tohru Ohmori, Motoi Ohba, Satoru Arata, Yasunori Murata, Sojiro Kusumoto, Koichi Ando, Hiroo Ishida, Tsukasa Ohnishi, Yasutsuna Sasaki
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with significant responses in non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations. However, acquired resistance to reversible EGFR-TKIs remains a major obstacle. In particular, while the second-generation irreversible EGFR-TKI afatinib is currently used for treating NSCLC patients, the mechanisms underlying acquired afatinib resistance remain poorly understood. Here, heterogeneous mechanisms of acquired resistance were identified following long-term exposure to increasing doses of afatinib in EGFR mutant lung adenocarcinoma PC9 cells...
March 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28287730/discovery-of-n-3r-4r-4-fluoro-1-6-3-methoxy-1-methyl-1h-pyrazol-4-yl-amino-9-methyl-9h-purin-2-yl-pyrrolidine-3-yl-acrylamide-pf-06747775-through-structure-based-drug-design-a-high-affinity-irreversible-inhibitor-targeting-oncogenic-egfr-mutants-with-selectivity
#8
Simon Planken, Douglas Carl Behenna, Sajiv K Nair, Theodore Otto Johnson, Asako Nagata, Chau Almaden, Simon Bailey, T Eric Ballard, Louise Bernier, Hengmiao Cheng, Sujin Cho-Schultz, Deepak Dalvie, Judith G Deal, Dac M Dinh, Martin P Edwards, Rose Ann Ferre, Ketan S Gajiwala, Michelle D Hemkens, Robert S Kania, John C Kath, Jean Matthews, Brion W Murray, Sherry Niessen, Suvi T M Orr, Mason Pairish, Neal W Sach, Hong Shen, Manli Shi, James Solowiej, Khanh Tran, Elaine Tseng, Paolo Vicini, Yuli Wang, Scott L Weinrich, Ru Zhou, Michael Zientek, Longqing Liu, Yiqin Luo, Shuibo Xin, Chengyi Zhang, Jennifer Anne Lafontaine
Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR-mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants was recently disclosed1...
March 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28287083/brigatinib-combined-with-anti-egfr-antibody-overcomes-osimertinib-resistance-in-egfr-mutated-non-small-cell-lung-cancer
#9
Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance...
March 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28285689/mutations-in-tp53-pik3ca-pten-and-other-genes-in-egfr-mutated-lung-cancers-correlation-with-clinical-outcomes
#10
Paul A VanderLaan, Deepa Rangachari, Susan M Mockus, Vanessa Spotlow, Honey V Reddi, Joan Malcolm, Mark S Huberman, Loren J Joseph, Susumu S Kobayashi, Daniel B Costa
INTRODUCTION: The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. METHODS: We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs)...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285688/plasma-epidermal-growth-factor-receptor-mutation-testing-with-a-chip-based-digital-pcr-system-in-patients-with-advanced-non-small-cell-lung-cancer
#11
Norimitsu Kasahara, Hirotsugu Kenmotsu, Masakuni Serizawa, Rina Umehara, Akira Ono, Yasushi Hisamatsu, Kazushige Wakuda, Shota Omori, Kazuhisa Nakashima, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Yasuhiro Koh, Keita Mori, Masahiro Endo, Takashi Nakajima, Masanobu Yamada, Masatoshi Kusuhara, Toshiaki Takahashi
OBJECTIVES: Epidermal growth factor receptor (EGFR) mutation testing is a companion diagnostic to determine eligibility for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Recently, plasma-based EGFR testing by digital polymerase chain reaction (dPCR), which enables accurate quantification of target DNA, has shown promise as a minimally invasive diagnostic. Here, we aimed to evaluate the accuracy of a plasma-based EGFR mutation test developed using chip-based dPCR-based detection of 3 EGFR mutations (exon 19 deletions, L858R in exon 21, and T790M in exon 20)...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285685/combination-treatment-with-erlotinib-and-ampelopsin-overcomes-erlotinib-resistance-in-nsclc-cells-via-the-nox2-ros-bim-pathway
#12
Seung-Woo Hong, Nam-Sook Park, Min Hye Noh, Ju A Shim, Byul-Nim Ahn, Yeong Seok Kim, Daejin Kim, Hyun-Kyung Lee, Dae Young Hur
OBJECTIVES: Erlotinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), has been shown to have a dramatic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the presence of primary resistance or acquired resistance to EGFR-TKI is the most common reason for switching to other anti-cancer agents. Even though there are newer agents that have activity in the presence of the T790M mutation, identification of potential agents that could overcome resistance to EGFR-TKI is still needed for the treatment of NSCLC patients...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28285073/development-of-an-uplc-ms-ms-method-for-quantification-of-avitinib-ac0010-and-its-five-metabolites-in-human-cerebrospinal-fluid-application-to-a-study-of-the-blood-brain-barrier-penetration-rate-of-non-small-cell-lung-cancer-patients
#13
Weicong Wang, Xin Zheng, Hanping Wang, Lu Wang, Ji Jiang, Pei Hu
Avitinib (AC0010) is a mutant-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), designed to be a targeted therapeutic agent for non-small cell lung cancer (NSCLC) patients harboring EGFR active and T790M resistant mutations. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of Avitinib and its five metabolites (M1, M2, M4, M7, MII-6) in human cerebrospinal fluid (CSF). The samples were purified by protein precipitation and separated on a BEH C18 column (2...
March 4, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28282122/discovery-of-r-1-3-4-amino-3-3-chloro-4-pyridin-2-ylmethoxy-phenyl-1h-pyrazolo-3-4-d-pyrimidin-1-yl-piperidin-1-yl-prop-2-en-1-one-chmfl-egfr-202-as-a-novel-irreversible-egfr-mutants-kinase-inhibitor-with-a-distinct-binding-mode
#14
Aoli Wang, Xixiang Li, Hong Wu, Fengming Zou, Xiao-E Yan, Cheng Chen, Chen Hu, Kailin Yu, Wenchao Wang, Peng Zhao, Jiaxin Wu, Ziping Qi, Wei Wang, Beilei Wang, Li Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Jing Liu, Qingsong Liu
Based on Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered a novel EGFR inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02), especially it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-Helix-out" inactive EGFR conformation...
March 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28274743/tolerable-and-effective-combination-of-full-dose-crizotinib-and-osimertinib-targeting-met-amplification-sequentially-emerging-after-t790m-positivity-in-egfr-mutant-non-small-cell-lung-cancer
#15
Emily York, Marileila Varella-Garcia, Tami J Bang, Dara L Aisner, D Ross Camidge
No abstract text is available yet for this article.
March 5, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28272214/genetic-characterization-drives-personalized-therapy-for-early-stage-non-small-cell-lung-cancer-nsclc-patients-and-survivors-with-metachronous-second-primary-tumor-mst-a-case-report
#16
Xingchen Ding, Linlin Wang, Xijun Liu, Xindong Sun, Jinming Yu, Xue Meng
RATIONALE: The pathogenesis and progression of lung cancer is a complicated process in which many genes take part. But molecular gene testing is typically only performed in advanced-stage non-squamous non-small-cell lung cancer (NSCLC). The value of tyrosine kinase inhibitors (TKI) administration is not widely recognized with respect to early-stage NSCLC. PATIENT CONCERNS: Here, we present a case of a man, heavy smoker who initially presented with stage IA lung adenocarcinoma (LADC)...
March 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28271038/successful-crizotinib-monotherapy-in-egfr-mutant-lung-adenocarcinoma-with-acquired-met-amplification-after-erlotinib-therapy
#17
Katsuhiro Yoshimura, Naoki Inui, Masato Karayama, Yusuke Inoue, Noriyuki Enomoto, Tomoyuki Fujisawa, Yutaro Nakamura, Kengo Takeuchi, Haruhiko Sugimura, Takafumi Suda
MET is a driver oncogene in non-small-cell lung cancer (NSCLC), and its amplification is associated with acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. A 56-year-old Japanese male with lung adenocarcinoma harboring an EGFR exon 21 L858R mutation received erlotinib to which he responded for 12 months. After disease progression, re-biopsy analyses revealed newly developed MET amplification. Neither EGFR exon 20 T790M mutation nor MET exon 14 mutations were detected...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28245967/pulsatile-erlotinib-in-egfr-positive-non-small-cell-lung-cancer-patients-with-leptomeningeal-and-brain-metastases-review%C3%A2-of%C3%A2-the-literature
#18
REVIEW
Joan How, Janelle Mann, Andrew N Laczniak, Maria Q Baggstrom
Patients with epidermal growth factor receptor (EGFR)-positive (EGFR(+)) non-small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients...
February 9, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28243590/second-line-treatment-of-nsclc-the-pan-erbb-inhibitor-afatinib-in-times-of-shifting-paradigms
#19
REVIEW
Jens Köhler
In contrast to the established role of epidermal growth factor receptor (EGFR) inhibitors for the first-line treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR blockade and of EGFR molecular testing in the second-line treatment remains less clear. The irreversible pan-ErbB family inhibitor afatinib (Gi(l)otrif(®)) was recently FDA- and EMA-approved for the second-line treatment of NSCLC with squamous cell histology irrespective of the EGFR mutational status (LUX-Lung 8)...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28238614/synthesis-and-in-vitro-biological-evaluation-of-novel-quinazoline-derivatives
#20
Yaling Zhang, Ying Zhang, Juan Liu, Li Chen, Lijun Zhao, Baolin Li, Wei Wang
A series of novel 4-arylamino-6-(5-substituted furan-2-yl)quinazoline derivatives were designed, synthesized and evaluated on biological activities in vitro. Compound 2a, 3a and 3c exhibited highly anti-proliferation activities on all tested tumor cell lines including SW480, A549, A431 and NCI-H1975 cells. Especially, compound 2a not only exhibited strong anti-proliferation activities against the tumor cell lines which expressed wild type or mutant EGFR(L858R/T790M), but also showed the most potent inhibitory activity toward wild type EGFR (IC50=5...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
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