From the Departments of Internal Medicine and Developmental Biology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to James Brugarolas, MD, PhD, Departments of Internal Medicine and Developmental Biology and Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9133; e-mail: james.brugarolas{at}utsouthwestern.edu
Overview: The tumor suppressor gene von Hippel-Lindau (VHL) is frequently inactivated in renal cell carcinoma (RCC) of clear cell type. VHL inactivation results in inappropriate activation of the hypoxia-inducible factor (HIF) transcription factors with consequent upregulation of angiogenic factors, including the vascular endothelial growth factor (VEGF). This discovery set the foundation for the clinical evaluation in RCC of inhibitors of VEGF, such as bevacizumab, as well as inhibitors of the principal VEGF angiogenic receptor, VEGFR2. Mammalian target of rapamycin (mTOR, referring to mTOR complex 1 [mTORC1]) has recently emerged as a target in RCC. Mutations disrupting the mTORC1 proximal negative regulator, a complex formed by the tuberous sclerosis complex (TSC) 1 and 2 proteins, result in an inherited predisposition to benign tumors and RCC. At the cellular level, TSC1/TSC2 inactivation leads to the mTORC1-dependent upregulation of protein synthesis and of HIF. mTOR functions as a serine/threonine protein kinase and it forms part of a second complex, mTORC2, with different subunit composition, different substrates, different functions, and differential inhibition by rapamycin (also called sirolimus). Rapamycin (in complex with FK506-binding protein 12kDa) solely binds to and thereby inhibits mTORC1, but mTORC2 may be indirectly inhibited in some cell types. The importance of mTOR in RCC has now been established, with two phase III trials of two rapamycin derivatives showing improved outcomes for patients with RCC.
