Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC.
Biomarkers, Tumor
/ genetics
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Drug Resistance, Neoplasm
/ genetics
Exons
Gene Expression Regulation, Neoplastic
/ drug effects
High-Throughput Nucleotide Sequencing
Humans
Lung Neoplasms
/ drug therapy
Molecular Targeted Therapy
Mutation
Prognosis
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-met
/ antagonists & inhibitors
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
03
11
2019
revised:
03
01
2020
accepted:
04
02
2020
pubmed:
9
2
2020
medline:
7
9
2021
entrez:
9
2
2020
Statut:
ppublish
Résumé
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 Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS). 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 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.
Identifiants
pubmed: 32034073
pii: 1078-0432.CCR-19-3608
doi: 10.1158/1078-0432.CCR-19-3608
doi:
Substances chimiques
Biomarkers, Tumor
0
Protein Kinase Inhibitors
0
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2615-2625Subventions
Organisme : NCI NIH HHS
ID : R01 CA203636
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA209414
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222823
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.