Targeting the Hepatocyte Growth Factor/c-Met Signaling Pathway in Renal Cell Carcinoma

The product of a proto-oncogene, the c-Met protein is a transmembrane receptor tyrosine kinase. Its only known ligand, hepatocyte growth factor/scatter factor, regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. Dysregulation of c-Met and hepatocyte growth factor have been observed in both clear cell and non-clear cell renal cell carcinomas (RCCs), although only papillary RCCs harbor activating mutations in the MET gene. In clear cell RCC, there is evidence of a direct link between loss of von Hippel-Lindau and up-regulation of c-Met. As in other cancers, high expression of c-Met correlates with worse outcomes in RCC. In vitro and in vivo preclinical RCC models demonstrate cancer control with small molecule and antibodies against c-Met. Given these findings, the c-Met pathway is a logical therapeutic target in RCC, and several agents are in clinical testing with early signs of efficacy.