scholarly journals Resistance mechanisms to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in lung adenocarcinoma cells harboring the EGFR-T790M mutation

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO4-6-22
Author(s):  
Kaori Nakatani ◽  
Toshimitsu Yamaoka ◽  
Tohru Ohmori ◽  
Motoi Ohba ◽  
Ken-ichi Fujita ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Third Generation ◽  
T790m Mutation ◽  
Adenocarcinoma Cells ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Lung Adenocarcinoma Cells ◽  
Egfr T790m

Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20576-e20576
Author(s):  
Ying Jin ◽  
Jianjun Zhang ◽  
Ming Chen ◽  
Yang Shao ◽  
Xun Shi ◽  
...  
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Targeted Next Generation Sequencing ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr T790m

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.

scholarly journals Ratio of T790M to EGFR-activating mutation predicts response of osimertinib in 1st or 2nd - generation EGFR-TKI-refractory NSCLC

2021 ◽  
Author(s):  
Motohiro Tamiya ◽  
Akihiro Tamiya ◽  
Norio Okamoto ◽  
Yoshihiko Taniguchi ◽  
Kazumi Nishino ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
T790m Mutation ◽  
Biopsy Tissue ◽  
Group Methods ◽  
Activating Mutation ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Response Group ◽  
Egfr Tki

Abstract Background: Afatinib followed by osimertinib (Afa group) may reportedly provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (1st-G group). Methods: We studied 111 consecutive patients with T790M mutation-positive NSCLC who were treated with osimertinib after progression following 1st- or 2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed T790M ratio with the re-biopsy tissue, obtained after EGFR-TKI resistance using droplet digital polymerase chain reaction, and investigate whether afatinib prifies the T790M mutation more than 1st-G EGFR-TKI.Results: Among the 60 patients with preserved re-biopsy tissues, we analyzed 38 patients whose re-biopsy tissue had adequate DNA content. Eleven patients in the Afa group had 81.8% of response rate, and 27 patients in the 1st-G group had 85.2% with RR. The mean T790M ratio was 0.3643. The T790M ratio in those with response of the osimertinib group was significantly higher than in those with non-response group (p=0.0272) and was similar in the Afa and 1st-G group (p=0.9693).Conclusion: T790M ratio significantly correlated with osimertinib response and T790M ratio was similar between the 1st and 2nd -G EGFR-TKIs in 1st or 2nd -G EGFR-TKI-refractory tumors.

scholarly journals CM93, a novel covalent small molecule inhibitor targeting lung cancer with mutant EGFR

2020 ◽  
Author(s):  
Qiwei Wang ◽  
Jing Ni ◽  
Tao Jiang ◽  
Hwan Geun Choi ◽  
Tinghu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
T790m Mutation ◽  
Activating Mutations ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutant ◽  
Egfr Tki

AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have provided successful targeted therapies for patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Osimertinib (AZD9291) is a third-generation irreversible EGFR TKI that has received regulatory approval for overcoming resistance mediated by the EGFR T790M mutation as well as a first-line treatment targeting EGFR activating mutations. However, a significant fraction of patients cannot tolerate the adverse effect associated with AZD9291. In addition, brain metastases are common in patients with NSCLN and remain a major clinical challenge. Here, we report the development of a novel third-generation EGFR TKI, CM93. Compared to AZD9291, CM93 exhibits improved lung cancer targeting and brain penetration and has demonstrated promising antitumor efficacy in mouse models of both EGFR-mutant NSCLC orthotopic and brain metastases. In addition, we find that CM93 confers superior safety benefits in mice. Our results demonstrate that further evaluations of CM93 in clinical studies for patients with EGFR-mutant NSCLC and brain metastases are warranted.

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