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• W2306529657 abstract "The PI3K-AKT pathway is hyperactivated in many human cancers, and several drugs to inhibit this pathway are currently being tested in various pre-clinical and clinical trials. It has been shown that pharmacological inhibition of the PI3K-AKT pathway results in feedback activation of other oncogenic signaling pathways, which likely will limit the clinical utilization of these inhibitors in cancer treatment. However, the underlying mechanisms of such feedback regulation remain incompletely understood. The PI3K-AKT pathway is a validated therapeutic target in renal cell carcinoma (RCC). Here we show that FoxO transcription factors serve to promote AKT phosphorylation at Ser473 in response to the treatment of NVP-BEZ235, a PI3K/mTOR dual inhibitor, in renal cancer cells. Inactivation of FoxO attenuated NVP-BEZ235-induced AKT Ser473 phosphorylation, and rendered renal cancer cells more susceptible to NVP-BEZ235-mediated cell growth suppression in vitro and tumor shrinkage in vivo. Mechanistically, we showed that FoxOs upregulated the expression of Rictor, an essential component of mammalian target of rapamycin complex 2 (mTORC2), in response to NVP-BEZ235 treatment, and revealed that Rictor is a key downstream target of FoxOs in NVP-BEZ235-mediated feedback regulation. We also show that FoxOs similarly modulate the feedback response on AKT Ser473 phosphorylation and renal tumor growth by the treatment of other PI3K or AKT inhibitors, such as MK-2206. Together, our study reveals a novel mechanism of PI3K-AKT inhibition-mediated feedback regulation. Importantly, a recent RCC clinical trial with MK-2206 revealed a dichotomous response in renal cancer patients: a subset of patients had dramatic tumor reduction, while another subset of RCC patients showed no decrease in tumor growth rate, and had a very short progression free survival. We will discuss our work to determine the expression/activation status of the FoxO-Rictor-AKT signaling axis in renal cancer patients receiving AKT inhibitor treatment, which may identify FoxO as a novel biomarker to stratify RCC patients for PI3K or AKT inhibitor treatment. Citation Format: Boyi Gan. The roles of FoxO transcription factors in mediating AKT activation and renal tumor growth in response to pharmacological inhibition of the PI3K-AKT pathway. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B06." @default.
• W2306529657 created "2016-06-24" @default.
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• W2306529657 date "2015-07-01" @default.
• W2306529657 modified "2023-09-27" @default.
• W2306529657 title "Abstract B06: The roles of FoxO transcription factors in mediating AKT activation and renal tumor growth in response to pharmacological inhibition of the PI3K-AKT pathway" @default.
• W2306529657 doi "https://doi.org/10.1158/1538-8514.pi3k14-b06" @default.
• W2306529657 hasPublicationYear "2015" @default.
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