Modulation of Akt/mTOR Signaling Overcomes Sunitinib Resistance in Renal and Prostate Cancer Cells
Menée sur des lignées cellulaires de cancer du rein et de la prostate, cette étude montre que, en restaurant l'expression de PTEN, divers inhibiteurs d'éléments de la voie de signalisation Akt/mTOR permettent de surmonter une résistance au sunitinib
Tyrosine kinase inhibitors (TKIs) exhibit impressive activity against advanced renal cell carcinoma. However, recent clinical studies have demonstrated an equivocal response to sunitinib in patients with castration-resistant prostate cancer. The tumor suppressor phosphatase and tensin homolog (PTEN) acts as a gatekeeper of the PI3K/Akt/mTOR cell-survival pathway. Our experiments demonstrate 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 anti-angiogenic actions.
http://mct.aacrjournals.org/content/early/2012/04/17/1535-7163.MCT-11-0907.abstract 2012