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Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer

Magda Bahcall1, Mark M Awad1, Lynette M Sholl2

  • 1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|August 4, 2018
PubMed
Abstract

Insights

Acquired KRAS amplification drives crizotinib resistance in MET exon 14 mutant NSCLC. Dual MET/PI3K inhibition effectively overcomes this resistance, offering a promising therapeutic strategy for non-small cell lung cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MET inhibitors are effective for MET exon 14 mutant non-small cell lung cancer (NSCLC).
  • Drug resistance limits long-term efficacy of MET inhibitors.
  • Acquired KRAS amplification is an emerging mechanism of resistance.

Purpose of the Study:

  • Characterize acquired wild-type KRAS amplification as a mechanism of crizotinib resistance in MET exon 14 mutant NSCLC.
  • Investigate the molecular signaling pathways involved in KRAS-mediated resistance.
  • Propose and evaluate a combination therapy to overcome crizotinib resistance.

Main Methods:

  • Established patient-derived cell line and xenograft (PDX) models from crizotinib-resistant tumors.
  • Analyzed molecular signaling in parental and KRAS-silenced cell lines.
  • Assessed sensitivity to ligand stimulation and quantified EGFR ligand expression.
  • Screened drug combinations for efficacy in vitro and in vivo.

Main Results:

  • KRAS amplification is a recurrent event in crizotinib-resistant MET exon 14 mutant NSCLC.
  • KRAS amplification uncouples MET from downstream effectors and induces PI3K signaling.
  • Resistance involves hypersensitivity to EGFR ligand activation and reliance on PI3K signaling.
  • Dual MET/PI3K inhibition showed superior efficacy in preclinical models.

Conclusions:

  • Acquired KRAS amplification is a key mechanism of crizotinib resistance in MET exon 14 mutant NSCLC.
  • Dual MET/PI3K inhibition is a potential therapeutic strategy to overcome this resistance.
  • Targeting KRAS-mediated resistance pathways may improve outcomes for NSCLC patients.

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