Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor-dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds.