Treatment of renal cell carcinoma: mTOR inhibitors

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

mTOR participates in two complexes, called TORC1 and TORC2 [179]. The former can be inhibited with rapamycin-like drugs. Two such drugs, temsirolimus and everolimus, have been FDA approved for the treatment of renal cell carcinoma based on positive randomized clinical trial data [180, 181]. In theory the activity of these agents reflects direct effects on tumor cells, including modulation of HIF [182], and effects downstream of VEGF signaling in endothelial cells (see below). In preclinical models, VHL-/renal carcinoma lines are more sensitive to rapamycin than are their pVHL-proficient counterparts [183]. As noted above, preliminary data suggest that concurrent mutations of the PI3K-MTOR pathway are enriched among renal carcinoma patients who exhibit the greatest clinical benefit from rapamycinlike drugs [170].

Two factors might, however, limit the effectiveness of rapamycin-like drugs in the treatment of renal cell carcinoma. First, the TORC1 complex feedback inhibits signaling by certain receptor tyrosine kinases [184, 185, 185a, 186–188]. As a result, treatment of tumor cells with rapamycin-like drugs can cause a paradoxical increase in receptor kinase activity leading to activation of TORC2, which is relatively rapamycin resistant, PI3K, and AKT, all of which might promote tumor growth [184, 185, 185a, 186–188]. Second, inhibition of TORC1 appears to preferentially inhibit HIF1a, which as argued above appears to act a renal cell carcinoma suppressor, rather than HIF2a [189]. In contrast, inhibition of TORC2 preferentially affects HIF2a [189]. Secondgeneration, ATP-like, mTOR inhibitors can inhibit both TORC1 and TORC2 and hence might be more active than rapamycin-like drugs in the treatment of clear cell renal carcinoma [190, 191]. Emerging preclinical data support such a view [192].

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