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https://www.readbyqxmd.com/read/27923840/osimertinib-for-the-treatment-of-metastatic-epidermal-growth-factor-t970m-positive-non-small-cell-lung-cancer
#1
Sean Khozin, Chana Weinstock, Gideon M Blumenthal, Joyce Cheng, Kun He, Luning Zhuang, Hong Zhao, Rosane Charlab Orbach, Ingrid Fan, Patricia Keegan, Richard Pazdur
On November 13, 2015, FDA granted accelerated approval to osimertinib (TAGRISSO™; AstraZeneca), a breakthrough therapy-designated drug for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, with progression on or after EGFR tyrosine kinase inhibitor therapy. Approval was based on durable tumor response rates in two single-arm, multicenter trials: the dose extension cohort of a first-in-human trial (AURA extension; n=201) and a fixed-dose, activity-estimating trial (AURA2; n=210)...
December 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27923714/brief-report-acquired-braf-v600e-mutation-as-resistant-mechanism-after-treatment-with-osimertinib
#2
Chao-Chi Ho, Wei-Yu Liao, Chih-An Lin, Jin-Yuan Shih, Chong-Jen Yu, James Chih-Hsin Yang
INTRODUCTION: AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a resistant mechanism in patients after osimertinib treatment. METHODS: Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib...
December 3, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27922678/a-novel-rapid-point-of-care-test-for-lung-cancer-patients-to-detect-epidermal-growth-factor-receptor-gene-mutations-by-using-real-time-droplet-pcr-and-fresh-liquid-cytology-specimens
#3
Shiho Asaka, Akihiko Yoshizawa, Kazuyuki Matsuda, Akemi Yamaguchi, Hiroshi Yamamoto, Takayuki Shiina, Rie Nakata, Kaoru Ogawa, Meng Zhang, Takayuki Honda
Epidermal growth factor receptor gene (EGFR) mutations are associated with response to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). We developed a novel, rapid EGFR mutation assay using a real-time droplet-polymerase chain reaction machine (EGFR d-PCR assay). The purpose of this study was to validate the performance of the EGFR d-PCR assay using fresh liquid cytology specimens. We analyzed three major EGFR mutations (L858R in exon 21, E746_A750del in exon 19 and T790M in exon 20) in 80 fresh liquid cytology specimens of adenocarcinoma (ADC) or NSCLC-not otherwise specified (NOS) via the EGFR d-PCR assay and conventional real-time PCR assay using the therascreen® EGFR RGQ PCR kit (Therascreen assay)...
December 2, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27920501/three-generations-of-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-developed-to-revolutionize-the-therapy-of-lung-cancer
#4
REVIEW
Haijun Zhang
Lung cancer, ~80%-85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm(+)), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27913578/characterization-of-egfr-t790m-l792f-and-c797s-mutations-as-mechanisms-of-acquired-resistance-to-afatinib-in-lung-cancer
#5
Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib...
December 2, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27912836/epidermal-growth-factor-receptor-mutated-advanced-non-small-cell-lung-cancer-a-changing-treatment-paradigm
#6
REVIEW
Suchita Pakkala, Suresh S Ramalingam
Activating mutations in the epidermal growth factor receptor (EGFR) are present in approximately 15% of US patients with lung adenocarcinoma. EGFR tyrosine kinase inhibitors are associated with high response rate and progression-free survival for patients with non-small cell lung cancer with this genotype. Gefitinib, erlotinib, and afatinib are the EGFR tyrosine kinase inhibitors that are presently in clinical use. Understanding resistance mechanisms has led to the identification of a secondary mutational target, T790M, in more than half of patients, for which osimertinib has been approved...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27912760/update-on-recent-preclinical-and-clinical-studies-of-t790m-mutant-specific-irreversible-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors
#7
REVIEW
Bin-Chi Liao, Chia-Chi Lin, Jih-Hsiang Lee, James Chih-Hsin Yang
The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy...
December 3, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27910964/osimertinib-a-third-generation-tyrosine-kinase-inhibitor-targeting-non-small-cell-lung-cancer-with-egfr-t790m-mutations
#8
C E McCoach, A Jimeno
Oncogenic driver mutations in the epidermal growth factor receptor (EGFR) gene have provided a focus for effective targeted therapy. Unfortunately, all patients eventually develop resistance to frontline therapy with EGFR tyrosine kinase inhibitors (TKIs). The majority of patients develop a large subclonal population of tumor cells with a T790M mutation that renders these cells resistant to first-generation TKIs. Osimertinib is a third-generation EGFR TKI that was designed to overcome resistance from T790M mutations...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27895798/exploring-the-impact-of-egfr-t790m-neighboring-snps-on-arms-based-t790m-mutation-assay
#9
Sanpeng Xu, Yaqi Duan, Liping Lou, Fengjuan Tang, Juan Shou, Guoping Wang
The present study aimed to explore the influence of T790M neighboring single nucleotide polymorphism (SNP) on the sensitivity of amplification refractory mutation system (ARMS)-based T790M mutation assay. Three ARMS-quantitative polymerase chain reaction (qPCR) systems (system 1 had a forward ARMS primer without rs1050171, system 2 included a forward ARMS primer with rs1050171 and system 3 contained the above two forward ARMS primers) were used to detect the T790M mutation in two series plasmid samples and genomic DNA (gDNA) of the cell line H1975...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895763/small-cell-lung-cancer-transformation-and-the-t790m-mutation-a-case-report-of-two-acquired-mechanisms-of-tki-resistance-detected-in-a-tumor-rebiopsy-and-plasma-sample-of-egfr-mutant-lung-adenocarcinoma
#10
Greta Alì, Rossella Bruno, Mirella Giordano, Irene Prediletto, Letizia Marconi, Simonetta Zupo, Franco Fedeli, Alessandro Ribechini, Antonio Chella, Gabriella Fontanini
The present study describes the case of a 45-year-old man diagnosed with metastatic lung adenocarcinoma, which harbored a deletion within exon 19 of the epidermal growth factor receptor (EGFR) gene. The patient was subsequently treated with gefitinib (250 mg/day orally from May 2013 to March 2014), but developed acquired resistance to the drug following 11 months of treatment. Tumor burden molecular analysis was performed on a tumor rebiopsy and plasma sample, and histological analysis was also performed on the tumor rebiopsy...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27891677/staurosporine-scaffold-based-rational-discovery-of-the-wild-type-sparing-reversible-inhibitors-of-egfr-t790m-gatekeeper-mutant-in-lung-cancer-with-analog-sensitive-kinase-technology
#11
Xiaoyun Song, Xingcai Liu, Xi Ding
The human epidermal growth factor receptor (EGFR) has been established as an attractive target for lung cancer therapy. However, an acquired EGFR T790M gatekeeper mutation is frequently observed in patients treated with first-line anticancer agents such as gefitinib and erlotinib to cause drug resistance, largely limiting the application of small-molecule kinase inhibitors in EGFR-targeted chemotherapy. Previously, the reversible pan-kinase inhibitor staurosporine and its several analogs such as Gö6976 and K252a have been reported to selectively inhibit the EGFR T790M mutant (EGFR(T790M) ) over wild-type kinase (EGFR(WT) ), suggesting that the staurosporine scaffold is potentially to develop the wild-type sparing reversible inhibitors of EGFR(T790M) ...
November 28, 2016: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/27885838/osimertinib-for-egfr-t790m-mutation-positive-non-small-cell-lung-cancer
#12
Kenzo Soejima, Hiroyuki Yasuda, Toshiyuki Hirano
Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3(rd) generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1(st) or 2(nd) generation EGFR-TKIs...
December 2, 2016: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/27870944/application-of-single-molecule-amplification-and-resequencing-technology-for-broad-surveillance-of-plasma-mutations-in-patients-with-advanced-lung-adenocarcinoma
#13
Zheng Wang, Gang Cheng, Xiaohong Han, Xinlin Mu, Yuhui Zhang, Di Cui, Chang Liu, Li Zhang, Zaiwen Fan, Lingyun Ma, Li Yang, Jing Di, David S Cram, Yuankai Shi, Dongge Liu
Liquid biopsy to access the circulating tumor DNA is a promising surrogate for invasive tumor genotyping. We designed a multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, and ALK plasma DNA variants in 103 patients with advanced lung adenocarcinoma. In validation studies using an analytical mutation standard, the sensitivity of the assay for EGFR mutation detection was at least 0.1% and specificity was 100%...
November 18, 2016: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27869781/molecular-docking-optimization-in-the-context-of-multi-drug-resistant-and-sensitive-egfr-mutants
#14
María Jesús García-Godoy, Esteban López-Camacho, José García-Nieto, Antonio J Nebro, José F Aldana-Montes
The human Epidermal Growth Factor (EGFR) plays an important role in signaling pathways, such as cell proliferation and migration. Mutations like G719S, L858R, T790M, G719S/T790M or T790M/L858R can alter its conformation, and, therefore, drug responses from lung cancer patients. In this context, candidate drugs are being tested and in silico studies are necessary to know how these mutations affect the ligand binding site. This problem can be tackled by using a multi-objective approach applied to the molecular docking problem...
November 19, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27866533/-lb100-reverses-the-acquired-resistance-to-gefitinib-in-lung-adenocarcinoma-cells-with-egfr-mutation
#15
S Shan, Y D Wang, T Ren
Objective: To investigate the possibility of the Protein Phosphatase 2A (PP2A) inhibitor, LB100, in reversing acquired resistance to gefitinib in lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation. Methods: Cell line NCI-H1975 and established primary culture cell line 44-1 with gefitinib resistance were sequenced to determine the mutation type of EGFR gene. Cells were treated with gefitinib alone or combined with LB100 to determine the half maximal inhibitory concentration (IC50), and sensitivity of 44-1 and NCI-1975 to gefitinib alone or combined with LB100 was compared...
November 15, 2016: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/27866520/-research-advancement-on-egfr-mutation-detection-of-cell-free-dna-and-tumor-cell-in-peripheral-blood-of-patients-with-non-small-cell-lung-cancer
#16
Yu Zhang, Yan Xu, Mengzhao Wang
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Epideral growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the most important treatments currently for advanced NSCLC patients harboring activating EGFR gene mutations, and achieve significant clinical efficacy. T790M mutation occurs in half of NSCLC patents with acquired EGFR-TKI resistance. Screening for EGFR gene mutations in histological and/or circulating tumor cell or DNA samples of NSCLC patients can identify patients who would have a response to EGFR-TKIs or acquire resistance during the treatment...
November 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/27864022/shikonin-inhibits-gefitinib-resistant-non-small-cell-lung-cancer-by-inhibiting-trxr-and-activating-the-egfr-proteasomal-degradation-pathway
#17
Xia Li, Xing-Xing Fan, Ze-Bo Jiang, Wings Ty Loo, Xiao-Jun Yao, Elaine Lai-Han Leung, Louis Wc Chow, Liang Liu
Non-small cell lung cancer (NSCLC) is the dominant type of lung cancer. Molecular targeting has highly improved the treatment efficacy of lung cancer, but new challenges have emerged, such as gefitinib-resistance and cancer recurrence. Therefore, new chemotherapeutic agents and treatment strategies are urgently needed. Shikonin is the main active component of a Chinese medicinal plant 'Zi Cao', which has been shown to exhibit powerful anti-cancer activity in certain types of cancer; however, its activity in gefitinib-resistant lung cancer has never been addressed...
November 15, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27861144/inhibition-of-oxidative-phosphorylation-suppresses-the-development-of-osimertinib-resistance-in-a-preclinical-model-of-egfr-driven-lung-adenocarcinoma
#18
Matthew J Martin, Cath Eberlein, Molly Taylor, Susan Ashton, David Robinson, Darren Cross
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27843631/unravelling-signal-escape-through-maintained-egfr-activation-in-advanced-non-small-cell-lung-cancer-nsclc-new-treatment-options
#19
REVIEW
Jordi Remon, Benjamin Besse
The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation...
2016: ESMO Open
https://www.readbyqxmd.com/read/27843613/mechanisms-of-resistance-to-egfr-targeted-drugs-lung-cancer
#20
REVIEW
Floriana Morgillo, Carminia Maria Della Corte, Morena Fasano, Fortunato Ciardiello
Despite the improvement in clinical outcomes derived by the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumours harbour EGFR-activating mutations, prognosis remains unfavourable because of the occurrence of either intrinsic or acquired resistance. We reviewed the published literature and abstracts of oral and poster presentations from international conferences addressing EGFR-TKIs resistance mechanisms discovered in preclinical models and in patients with NSCLC...
2016: ESMO Open
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