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

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...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2012-07, Vol.11 (7), p.1510-1517
Main Authors: Makhov, Peter B, Golovine, Konstantin, Kutikov, Alexander, Teper, Ervin, Canter, Daniel J, Simhan, Jay, Uzzo, Robert G, Kolenko, Vladimir M
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Cell Line, Tumor
Cytokines - genetics
Cytokines - metabolism
Drug Resistance, Neoplasm - genetics
Humans
Indoles - administration & dosage
Indoles - pharmacology
Kidney Neoplasms - enzymology
Kidney Neoplasms - genetics
Male
Mice
Mice, SCID
Prostatic Neoplasms - enzymology
Prostatic Neoplasms - genetics
Proto-Oncogene Proteins c-akt - metabolism
PTEN Phosphohydrolase - genetics
PTEN Phosphohydrolase - metabolism
Pyrroles - administration & dosage
Pyrroles - pharmacology
Signal Transduction - drug effects
TOR Serine-Threonine Kinases - metabolism
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.mct-11-0907