New Drugs
The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

https://doi.org/10.1016/j.ctrv.2020.102022Get rights and content
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Highlights

  • MET exon 14 skipping is a primary oncogenic driver sensitive to MET inhibition.

  • Selective MET inhibitors have potential for improved efficacy in selected patients.

  • Selective agents may have favorable tolerability compared with non-selective agents.

  • The sensitivity of MET exon 14 skipping tumors to these drugs is being established.

Abstract

Dysregulated activation of the MET tyrosine kinase receptor is implicated in the development of solid tumors and can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor (HGF), and the acquisition of activating mutations. The most common activating mutations cause exon 14 to be skipped during MET mRNA splicing. This in-frame deletion, known as MET exon 14, results in production of a shortened receptor that lacks a juxtamembrane domain but retains affinity for HGF. However, the negative regulatory function located within this protein sequence is lost, leading to receptor accumulation on the cell surface and prolonged activation by HGF. MET mutations causing exon 14 skipping appear to be true oncogenic drivers and occur in patients and tumors with distinct characteristics.

Increasing evidence suggests that tumors carrying such mutations are sensitive to MET inhibition, raising the hope that selective MET inhibitors will provide patients with optimal anticancer activity with minimal toxicity.

We discuss the prospects for selective MET inhibitors in the treatment of non-small cell lung cancer harboring MET exon 14 skipping.

Keywords

NSCLC
MET exon 14 skipping
MET inhibitor

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