Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer

Abstract

BackgroundPI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110α PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro.MethodsWe employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescence-based method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR.Resultsp85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multi-variable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC50s in the low ηM range and resultant PARP cleavage.ConclusionsHigh PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation.

Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells

“…We previously reported that combined treatment with Rapa and CN-A was also effective in inhibiting the growth of MDA-MB231 cells (17). As with recent reports (28,29), the potent well-known PI3K inhibitor LY294002 inhibited Rapa-induced phosphorylation of Akt (Ser473) (Fig. 7B) and was able to enhance the Rapa-induced growth inhibition of MCF-7 cells in our culture conditions (Fig.…”

“…We next examined the effects of a potent PI3K inhibitor LY294002 on Rapa-induced phosphorylation of Akt (Ser473) and Rapa-induced growth inhibition of MCF-7 cells. In agreement with previous reports (28,29), LY294002 (3 µM) alone significantly inhibited phosphorylation of both Akt (Ser473) and p70S6K (Fig. 7B).…”

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

“…This pathway is a prime target in radiotherapy, and inhibition of this cascade can induce autophagy and enhance the radiosensitivity of tumor cells. In fact, the dual PI3K/mTOR inhibitor NVP-BEZ235 exhibits promising effects against various tumors [42][43][44][45] . However, to date, research has not yet focused on the radiosensitization efficacy of NVP-BEZ235 in GSCs, which are a small subpopulation of GBM that exhibit higher radioresistance.…”

Metabolic syndrome and renal cell carcinoma

“…In some studies, researchers have detected low PTEN expression, and high expression of PI3K/mTOR, in clear cell RCC [97,98]. Further, high PI3K/mTOR expression seems to be associated with poorer prognosis [99,100]. Given the importance of mTOR for RCC, great progress has been made in targeting mTOR.…”