The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy.

Clark PE
Kidney Int. 2009 76 (9): 939-45

PMID: 19657325 · PMCID: PMC2963106 · DOI:10.1038/ki.2009.296

The basic biology underlying the development of clear-cell renal cell carcinoma (ccRCC) is critically dependent on the von Hippel-Lindau gene (VHL), whose protein product is important in the cell's normal response to hypoxia. Aberrations in VHL's function, either through mutation or promoter hypermethylation, lead to accumulation of the transcriptional regulatory molecule, hypoxia-inducible factor alpha (HIFalpha). HIFalpha can then dimerize with HIFbeta and translocate to the nucleus, where it will transcriptionally upregulate a series of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others. Binding of these ligands to their cognate receptors activates a series of kinase- dependent signaling pathways, including the RAF-MEK-ERK and phosphatidylinositol-3 kinase-AKT-mTOR pathways. Targeted agents developed and now approved for use in advanced ccRCC include humanized monoclonal antibodies against VEGF, small-molecule tyrosine kinase inhibitors, and inhibitors of mTOR. Understanding the biology of ccRCC is critical in understanding the current therapy for the disease and in developing novel therapeutics in the future. This review will provide an overview of the genetics of ccRCC, with an emphasis on how this has informed the development of the targeted therapeutics for this disease.

MeSH Terms (19)

Animals Antibodies, Monoclonal Antineoplastic Agents Aryl Hydrocarbon Receptor Nuclear Translocator Carcinoma, Renal Cell Drug Design Gene Expression Regulation, Neoplastic Humans Hypoxia-Inducible Factor 1, alpha Subunit Kidney Neoplasms Protein Kinase Inhibitors Protein Kinases Receptors, Vascular Endothelial Growth Factor Signal Transduction TOR Serine-Threonine Kinases Translational Medical Research Treatment Outcome Vascular Endothelial Growth Factor A Von Hippel-Lindau Tumor Suppressor Protein

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