The mammalian target of rapamycin (mTOR) is an important intermediary of the signaling transduction cascade that reacts to external nutrient abundance, to external growth factor and hormonal signaling, and to internal cellular energy levels. There are two major complexes formed with mTOR: mTORC1 and mTORC2. mTORC1 is rapamycin (also known as sirolimus) sensitive, and acts as a signaling intermediary for nutrient availability, energy levels, and growth factor signaling. mTORC2 is less well defined, and is capable of upregulating AKT activity. Two mammalian targets of rapamycin (mTOR) inhibitors were FDA approved for use in renal cell carcinoma (RCC) in the past 5 years. Temsirolimus, an intravenous sirolimus ester was shown to improve overall survival in a study of 626 patients with untreated metastatic RCC and poor risk features. Everolimus, an oral rapamycin analog, was shown to improve progression-free survival compared to placebo in patients with metastatic RCC who progressed on sorafenib, sunitinib, or both. New agents are being investigated that function upstream of mTOR to block activity of phosphoinositide-3 phosphate kinase (PI3K), AKT, or are capable of blocking mTORC1 and mTORC2 simultaneously.
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