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Makhov PB , Golovine K , Kutikov A , Teper E , Canter DJ , Simhan J , Uzzo RG , Kolenko VM
Modulation of Akt/mTOR Signaling Overcomes Sunitinib Resistance in Renal and Prostate Cancer Cells
Molecular Cancer Therapeutics. 2012 Jul;11(7) :1510-1517
PMID: WOS:000308021100013    PMCID: PMC 3491642   
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Abstract
Tyrosine kinase inhibitors exhibit impressive activity against advanced renal cell carcinoma. However, recent clinical studies have shown an equivocal response to sunitinib in patients with castration-resistant prostate cancer. The tumor suppressor PTEN acts as a gatekeeper of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR cell-survival pathway. Our experiments showed that PTEN expression inversely correlates with sunitinib resistance in renal and prostate cancer cells. Restoration of PTEN expression markedly increases sensitivity of tumor cells to sunitinib both in vitro and in vivo. In addition, pharmacologic manipulation of PI3K/Akt/mTOR signaling with PI3K/mTOR inhibitor, GDC-0980, mTOR inhibitor, temsirolimus, or pan-Akt inhibitor, GSK690693, was able to overcome sunitinib resistance in cancer cells. Our findings underscore the importance of PTEN expression in relation to sunitinib resistance and imply a direct cytotoxic effect by sunitinib on tumor cells in addition to its antiangiogenic actions. Mol Cancer Ther; 11(7); 1510-7. (c) 2012 AACR.
Notes
Makhov, Peter B. Golovine, Konstantin Kutikov, Alexander Teper, Ervin Canter, Daniel J. Simhan, Jay Uzzo, Robert G. Kolenko, Vladimir M. NIH grant[RO1 CA134463]; American Institute for Cancer Research Grant; Department of Defense, Physician Research Training Award This work was supported in part by the NIH grant RO1 CA134463 to V.M. Kolenko; the American Institute for Cancer Research Grant to R.G. Uzzo; the Department of Defense, Physician Research Training Award to A. Kutikov. 22 Amer assoc cancer research Philadelphia 995oy