Targeting HIF2α in Clear-Cell Renal Cell Carcinoma Christopher J. Ricketts, Daniel R. Crooks, W. Marston Linehan  Cancer Cell  Volume 30, Issue 4, Pages 515-517 (October 2016) DOI: 10.1016/j.ccell.2016.09.016 Copyright © 2016 Terms and Conditions

Figure 1 Targeted Therapies for Advanced Clear-Cell Renal Cell Carcinoma (A) The von Hippel-Lindau protein (VHL) is a component of the protein complex that includes Elongin B/C, Cullin 2, RING-box protein 1 (RBX1), and an E2 ubiquitin-conjugating enzyme (E2) that possesses ubiquitin ligase E3 activity and, in normoxia, degrades the HIF1α and HIF2α transcription factors. Inactivation of VHL in ccRCC results in stabilization of HIFs, dimerization with ARNT, and activation of the hypoxia response pathway. Current FDA-approved therapies for advanced ccRCC either target the activated components of the hypoxia response pathway (bevacizumab, sunitinib, sorafenib, pazopanib, axitinib, levantinib, and cabozantinib)—such as VEGF, the VEGF receptor, and the PDGF receptor—or target the mTOR pathway (temsirolimus and everolimus) to lower the levels of the HIF by inhibiting translation of de novo HIF protein. (B) The PT2399 HIF2α antagonist specifically inhibits the dimerization of HIF2α and ARNT, resulting in loss of expression of HIF2α targets, such as VEGF. (Adapted from Ricketts et al., 2016.) Cancer Cell 2016 30, 515-517DOI: (10.1016/j.ccell.2016.09.016) Copyright © 2016 Terms and Conditions