The MET/hepatocyte growth-factor (HGF) signaling pathway plays a key role in the 
processes of embryogenesis, wound healing, and organ regeneration. Aberrant 
activation of MET/HGF occurs through multiple mechanisms including gene 
amplification, mutation, protein overexpression, and abnormal gene splicing 
interrupting autocrine and paracrine regulatory feedback mechanisms. In many 
cancers including non-small-cell lung cancer, colorectal, gastric, renal, and 
hepatocellular cancer, dysregulation of MET may lead to a more aggressive cancer 
phenotype and may be a negative prognostic indicator. Successful therapeutic 
targeting of the MET/HGF pathway has been achieved using monoclonal antibodies 
against the MET receptor and its ligand HGF in addition to MET-specific and 
multitargeted small-molecule tyrosine-kinase inhibitors with several drugs in 
late-phase clinical trials including onartuzumab, rilotumumab, tivantinib, and 
cabozantinib. MET frequently interacts with other key oncogenic tyrosine kinases 
including epidermal growth-factor receptor (EGFR) and HER-3 and these 
interactions may be responsible for resistance to anti-EGFR therapies. 
Similarly, resistance to MET inhibition may be mediated through EGFR activation, 
or alternatively by increasing levels of MET amplification or acquisition of 
novel "gatekeeper" mutations. In order to optimize development of effective 
inhibitors of the MET/HGF pathway clinical trials must be enriched for patients 
with demonstrable MET-pathway dysregulation for which robustly standardized and 
validated assays are required.