Differentiating mTOR inhibitors in renal cell carcinoma.

PI3K/Akt/mTOR signalling is dysregulated in many cancers, including renal cell carcinoma (RCC), and activation of this pathway has been suggested to correlate with aggressive behavior and poor prognosis in RCC tumors. mTOR inhibition plays a principal role in the targeted treatment of many cancer types, including RCC. Although mTOR inhibitors share the same mechanism of action, differences in metabolism, formulation and dosing schedule underpin distinct PK/PD profiles such that they may be differentiated for use in a variety of treatment niches. Approved mTOR inhibitors temsirolimus and everolimus serve as important therapeutic options within the current RCC treatment paradigm, although their recommended applications differ in setting and patient population characteristics. Clinical practice guidelines recommend temsirolimus for use in treatment-naive patients with poor-prognosis metastatic RCC of any histology (predominant clear cell or non-clear cell histology). Everolimus provides a standard-of-care therapy for patients with metastatic RCC whose disease has progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. As therapeutic failure impacts the vast majority of patients with RCC, sequencing strategies of available agents or simultaneous targeting of multiple members of the PI3K/Akt/mTOR pathway may provide additional clinical benefit. Various classes of agents targeting the PI3K/Akt/mTOR pathway are currently being investigated, including mTORC1/mTORC2 kinase domain inhibitors, mTOR/PI3K dual inhibitors, PI3K-selective inhibitors, and programmed cell death 6 modulators. Clinical trials of mTOR inhibitors in a variety of tumor types are ongoing, and the role of mTOR inhibitors continues to evolve across the RCC treatment landscape.