Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer

Clin Cancer Res. 2020 Jan 15;26(2):439-449. doi: 10.1158/1078-0432.CCR-19-1667. Epub 2019 Sep 23.


Purpose: Although patients with advanced-stage non-small cell lung cancers (NSCLC) 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.

Experimental design: 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 with 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 cotreatment with crizotinib and the MEK inhibitor trametinib.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell-Free Nucleic Acids / blood
  • Cell-Free Nucleic Acids / genetics
  • Crizotinib / therapeutic use*
  • Exons*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • MAP Kinase Signaling System / genetics*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Mutation
  • Oncogene Protein p21(ras) / genetics*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / genetics*
  • Treatment Outcome
  • Tumor Cells, Cultured


  • Biomarkers, Tumor
  • Cell-Free Nucleic Acids
  • Protein Kinase Inhibitors
  • Crizotinib
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Oncogene Protein p21(ras)