von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology.

The most common form of kidney cancer is clear cell renal cell carcinoma (ccRCC). Biallelic VHL tumor suppressor gene inactivation is the usual initiating event in both hereditary (VHL Disease) and sporadic ccRCCs. The VHL protein, pVHL, earmarks the alpha subunits of the HIF transcription factor for destruction in an oxygen-dependent manner. Deregulation of HIF2 drives ccRCC pathogenesis. Drugs inhibiting the HIF2-responsive growth factor VEGF are now mainstays of ccRCC treatment. A first-in-class allosteric HIF2 inhibitor was recently approved for treating VHL Disease-associated neoplasms and appears active against sporadic ccRCC in early clinical trials.