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Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14–Mutant NSCLC

Authors :
Lynette M. Sholl
Geoffrey R. Oxnard
Giuseppe Lamberti
Ying-Chun Lo
Stephen R. Fairclough
Liam F. Spurr
Adem Albayrak
Deepti Venkatraman
Tom C. Nguyen
Renato Umeton
Yvonne Y. Li
Magda Bahcall
Pasi A. Jänne
Marina S.D. Milan
Mark M. Awad
Andrew D. Cherniack
Cloud P. Paweletz
Biagio Ricciuti
Gonzalo Recondo
Jianwei Che
Giulia Costanza Leonardi
Kristin S Price
Mizuki Nishino
Source :
Clinical Cancer Research. 26:2615-2625
Publication Year :
2020
Publisher :
American Association for Cancer Research (AACR), 2020.

Abstract

Purpose:Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14–mutant NSCLC.Experimental Design:Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).Results:A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14–mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.Conclusions:On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.

Details

ISSN :
15573265 and 10780432
Volume :
26
Database :
OpenAIRE
Journal :
Clinical Cancer Research
Accession number :
edsair.doi.dedup.....2f77a1442ed95a93dfcaa6ab0190cd23
Full Text :
https://doi.org/10.1158/1078-0432.ccr-19-3608