title: 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.
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Makhov
authors.forename: Konstantin
authors.initials: K
authors.lastname: Golovine
authors.forename: Alexander
authors.initials: A
authors.lastname: Kutikov
authors.forename: Ervin
authors.initials: E
authors.lastname: Teper
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Canter
authors.forename: Jay
authors.initials: J
authors.lastname: Simhan
authors.forename: Robert G
authors.initials: RG
authors.lastname: Uzzo
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Kolenko
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007211:Indoles; D011758:Pyrroles; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D000077210:Sunitinib