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MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in

Marie Fernandes1, Brynna Hoggard2, Philippe Jamme1

  • 1Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, France.

Molecular Oncology
|February 17, 2023
PubMed

Insights

MET exon 14 skipping mutations drive non-small-cell lung cancer (NSCLC) and TKI sensitivity. Human hepatocyte growth factor (hHGF) is required for METex14 oncogenicity, offering potential clinical implications for NSCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Exon skipping mutations in the MET receptor tyrosine kinase (METex14) are increasingly identified in cancers, including 3-4% of non-small-cell lung cancer (NSCLC).
  • Response rates to MET-tyrosine kinase inhibitors (TKIs) in NSCLC patients with METex14 alterations are only 50%, highlighting the need to understand the underlying mechanisms of oncogenicity and TKI sensitivity.
  • Previous preclinical models have not fully elucidated whether METex14 acts as a driver mutation or its requirement for hepatocyte growth factor (HGF) in oncogenicity.

Purpose of the Study:

  • To investigate the oncogenic role of METex14 mutations in non-small-cell lung cancer.
  • To determine the requirement of human hepatocyte growth factor (hHGF) for METex14-driven oncogenicity.
  • To establish a preclinical model for studying METex14-driven NSCLC and TKI sensitivity.

Main Methods:

  • Development of an isogenic METex14/WT model using CRISPR/Cas9 in nontransformed human lung cells.
  • In vitro assessment of anchorage-independent survival and motility.
  • In vivo tumorigenesis studies using a humanized HGF knock-in mouse model and analysis of patient tumor samples.

Main Results:

  • The METex14 alteration alone was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility, and in vivo tumorigenesis.
  • METex14-driven tumors were sensitive to MET-TKIs.
  • Human HGF (hHGF) was demonstrated to be essential for METex14 oncogenicity in vivo and was detected in METex14 NSCLC patient tumor cells.
  • Results suggest METex14 oncogenicity is not due to an escape from degradation.

Conclusions:

  • MET exon 14 skipping is a driver mutation in NSCLC, sufficient for oncogenicity and TKI sensitivity.
  • Human HGF is required for METex14 oncogenicity, representing a potential therapeutic target.
  • The developed isogenic model is valuable for preclinical studies of METex14-driven NSCLC.
Keywords:
hepatocyte growth factorlung cancerpreclinical modelstargeted therapiestranscriptomictyrosine kinase receptor

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