A better understanding of the pathophysiology and evolution of non-small cell 
lung cancer (NSCLC) has identified a number of molecular targets and spurred 
development of novel targeted therapeutic agents. The MET receptor tyrosine 
kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor 
cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of 
human cancers, including NSCLC. Amplification of MET has been reported in 
approximately 5%-22% of lung tumors with acquired resistance to small-molecule 
inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR 
inhibitors is likely mediated through downstream activation of the 
phosphoinositide 3-kinase /AKT pathway. Simultaneous treatment of resistant 
tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of 
downstream effectors of cell growth, proliferation, and survival, thereby 
overcoming acquired resistance to EGFR inhibitors. Development and preclinical 
testing of multiple agents targeting the HGF-MET pathway, including monoclonal 
antibodies targeting HGF or the MET receptor and small-molecule inhibitors of 
the MET tyrosine kinase, have confirmed the crucial role of this pathway in 
NSCLC. Several agents are now in phase III clinical development for the 
treatment of NSCLC. This review summarizes the role of MET in the 
pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and 
provides an update on progress in the clinical development of inhibitors of MET 
for treatment of NSCLC.