Format

Send to

Choose Destination
Clin Cancer Res. 2019 Sep 23. pii: clincanres.1667.2019. doi: 10.1158/1078-0432.CCR-19-1667. [Epub ahead of print]

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer.

Author information

1
Medical Oncology, Dana-Farber Cancer Institute.
2
Medicine, University of California, San Francisco.
3
Clinical Neurosciences and Oncology, University of Calgary.
4
Medical Affairs, Guardant Health, Inc.
5
Department of Medical Affairs, Guardant Health, Inc.
6
Department of Medicine, UF Cancer Center, University of Florida.
7
Division of Medical Oncology, Rabin Medical Center.
8
Molecular Oncology, Massachusetts General Hospital Cancer Center.
9
Cancer Center, Massachusetts General Hospital.
10
Department of Medicine, Harvard Medical School.
11
Dermatology and Pathology, University of California, San Francisco.
12
Pathology, University of Florida.
13
University of California, San Francisco.
14
Bioengineering and Therapeutic Sciences, University of California, San Francisco.
15
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
16
Hematology/ Oncology, University of California - San Francisco School of Medicine.
17
medical oncology, University of Colorado Cancer Center.
18
Internal Medicine, University of Colorado Anschutz Cancer Center.
19
Department of Medicine, UC San Diego Moores Cancer Center.
20
Department of Internal Medicine, University of California Davis School of Medicine.
21
Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco collin.blakely@ucsf.edu.

Abstract

PURPOSE:

While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.

METHODS:

Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC.

RESULTS:

Prominent co-occurring RAS-MAPK pathway gene alterations (e.g. in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared to EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib.

CONCLUSION:

Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center