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Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14–Mutant NSCLC
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Lung Neoplasms
Mutant
Drug resistance
medicine.disease_cause
03 medical and health sciences
Exon
0302 clinical medicine
Carcinoma, Non-Small-Cell Lung
Biomarkers, Tumor
medicine
Carcinoma
Humans
Molecular Targeted Therapy
Protein Kinase Inhibitors
Mutation
business.industry
High-Throughput Nucleotide Sequencing
Exons
Proto-Oncogene Proteins c-met
Prognosis
medicine.disease
respiratory tract diseases
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
Protein kinase domain
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
KRAS
business
Tyrosine kinase
Subjects
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