Mechanism of action of everolimus in renal cell carcinoma

The mammalian target of rapamycin (mTOR) is a strategic target for cancer therapy. This serine/threonine kinase is involved in the integration of signals from numerous growth factors and nutrients and regulates the mRNA translation of proteins that mediate cell growth, proliferation, metabolism, and angiogenesis. The pathways which impact mTOR signaling are dysregulated in many cancers, including renal cell carcinoma (RCC). In addition, for many patients, the pathogenesis of RCC is related to loss of function of the von Hippel-Lindau (VHL) gene, resulting in inappropriate accumulation of the hypoxia-inducible factor, HIF-1 alpha. The heterodimer of HIF-1 alpha and HIF-1 beta forms HIF-1, a transcription factor that regulates the production of mitogenic factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor-beta (PDGF-beta), and transforming growth factor-alpha (TGF-alpha). Because mTOR regulates the production of HIF-1 alpha, increased mTOR signaling in RCC may enhance the tumorigenic effects of loss of VHL. Therefore, inhibition of mTOR is particularly relevant in RCC. mTOR is located downstream of other therapeutic targets such as VEGF (target of bevacizumab) and VEGF receptor tyrosine kinases (targets of sorafenib and sunitinib), which provides opportunities for combination therapy and therapy in patients refractory to single agent treatments. Everolimus (RAD001), a synthetic, orally bioavailable analog of rapamycin, is a specific inhibitor of mTOR currently being developed for RCC and other types of cancer. This article will summarize the involvement of mTOR in RCC and the identified mechanisms by which mTOR inhibitors exert their antineoplastic effects, with a focus on everolimus.