Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Abstract

The hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers likely to be predictive of response. Whereas previous trials that focused on MET pathway-directed targeted therapy in unselected or MET-overexpressing NSCLC yielded largely negative results, more recent investigations focusing on MET exon 14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.

Keywords: MET amplification; MET exon 14 skipping alterations; MET inhibitor; MET overexpression; crizotinib; non-small cell lung cancer.

FIGURE 1

A. Timeline of discovery in lung cancers harboring alterations of the MET pathway. B. The MET receptor and selected MET pathway-directed targeted therapies CEP7, centromeric portion of chromosome 7; HGF, hepatocyte growth factor; IPT, immunoglobulin-plexin transcription; mAb, monoclonal antibody; MET, mesenchymal epithelial transition receptor; PSI, plexin semaphoring integrin domain; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor

FIGURE 2

The pathobiology of METex14 alterations and MET amplification CEP7, centromeric portion of chromosome 7; IPT, immunoglobulin-plexin transcription; MET, mesenchymal epithelial transition receptor; METex14, mesenchymal epithelial transition receptor exon 14; PSI, plexin semaphoring integrin domain