Targeting mTOR in renal cell carcinoma

The mammalian target of rapamycin (mTOR) is clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first‐line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression‐free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors. Cancer 2009;115(10 suppl):2313‐20. © 2009 American Cancer Society. Inhibitors of the mammalian target of rapamycin (mTOR) are effective treatment for many patients with advanced renal cell carcinoma (RCC). Temsirolimus increases overall survival in patients with metastatic RCC and multiple risk factors for short survival. Everolimus increases progression‐free survival in patients with metastatic RCC that has progressed after sunitinib, sorafenib, and other therapies. Newer clinical investigations that focus on the possibility of improving treatment outcomes involve combinations of an mTOR inhibitor with bevacizumab or sorafenib, agents active against RCC, but with different mechanisms of action. Possible mechanisms of resistance to mTOR inhibition have been identified, and may be reduced through combination of an mTOR inhibitor with other targeted agent