Targeting the Hepatocyte Growth Factor/c-Met Signaling... : The Cancer Journal (original) (raw)

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

From the Dana-Farber Cancer Institute, Dana 1230 Solid Tumor Oncology, Lank Center for Genitourinary Oncology, Boston, MA.

Conflicts of Interest: Dr. Harshman has been an advisor for Pfizer, Aveo and BMS and has done research for BMS and Novartis; and Dr. Choueiri has been an advisor for Pfizer, GSK, Aveo, Novartis, Genentech, Bayer/Onyx, and Exilexis and has done research for Pfizer, GSK, Aveo, Novartis, Genentech, Bayer/Onyx, Exilexis, and BMS.

Reprints: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, Dana 1230 Solid Tumor Oncology, Lank Center for Genitourinary Oncology, D1230, 450 Brookline Ave, Boston, MA 02215. E-mail: [email protected].

Abstract

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.