mTOR in renal cell cancer: modulator of tumor biology and therapeutic target.

Elucidation of the crucial role of the PI3K/Akt/mTOR pathway in the pathogenesis of cancer has led to the development of various drugs targeting this signaling cascade at distinct levels. mTOR, a serine/threonine kinase plays a pivotal role in coupling growth stimuli to cell cycle progression. There are two distinct macromolecular complexes of mTOR: mTORC1, which is rapamycin-sensitive and contains raptor; and mTORC2, which is rapamycin-insensitive and contains rictor. However, in recent preclinical studies a sustained exposure of cancer cells to rapamycin has been shown to inhibit the function of both mTORC1 and mTORC2 complexes. Downstream targets of these complexes, which involve HIF-1alpha and HIF-2alpha, cyclin D1 and PKC-alpha, are responsible for the activation of various intracellular processes leading to the activation of cell proliferation, and induction of angiogenesis, metastasis or chemoresistance. Since the biology of renal cell cancer (RCC) is tightly controlled by mTOR, targeted inhibition of mTOR function appeared to be a promising therapeutic approach for RCC patients. To date, results of two, large, Phase III clinical trials evaluating the efficacy of rapamycin derivatives (i.e., temsirolimus and everolimus) in the treatment of RCC have been published. First-line temsirolimus (CCI-779) administered to metastatic, poor-prognosis RCC patients significantly prolonged overall and progression-free survival when compared with IFN-alpha. Treatment of metastatic RCC patients refractory to tyrosine kinase inhibitors with everolimus (RAD-001) significantly prolonged progression-free survival when compared with placebo. Therapeutic strategies based on mTOR inhibition in RCC demonstrated a significant clinical activity. However, there are still patients refractory to mTOR inhibitors. Various molecular mechanisms of resistance to rapalogues have been identified and will have to be targeted simultaneously with mTOR in order to achieve a complete inhibition of signaling pathways crucial for the pathogenesis of RCC. Such clinical trials evaluating a combination of mTOR inhibitors with other targeted therapies are ongoing.