Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells.

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.

journal_name

Mol Cancer Ther

authors

Makhov PB,Golovine K,Kutikov A,Teper E,Canter DJ,Simhan J,Uzzo RG,Kolenko VM

doi

10.1158/1535-7163.MCT-11-0907

subject

Has Abstract

pub_date

2012-07-01 00:00:00

pages

1510-7

issue

7

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-11-0907

journal_volume

11

pub_type

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