MET overexpression and gene amplification in NSCLC: a clinical perspective

The transmembrane tyrosine kinase mesenchymal-epidermal transition (MET) receptor and its ligand, hepatocyte growth factor, also known as scatter factor, have recently been identified as novel promising targets in several human malignancies, including non-small cell lung cancer (NSCLC). Amplification, mutation, or overexpression of the MET gene can result in aberrant activation of the MET axis, leading to migration, invasion, proliferation, metastasis, and neoangiogenesis of cancer cells, suggesting that interfering with the MET/hepatocyte growth factor pathway could represent a potential antitumor strategy. While the role of MET mutations in NSCLC is not as yet fully understood, retrospective studies have shown that an increased MET gene copy number is a negative prognostic factor. In NSCLC, amplification of the MET gene is a relatively rare event, occurring in approximately 4% of patients not previously exposed to systemic therapies and in up to 20% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. In preclinical models, the presence of MET amplification is a predictor of high sensitivity to anti-MET compounds, and several agents have entered in clinical trials for patients having advanced disease, with promising results. The aim of the present review is to summarize available data on the role of MET in NSCLC and to describe therapeutic strategies under investigation.