Abstract A33: Utilizing insulin the treatment of prostate cancer with BKM120 abrogates the therapeutic effect of PI3K pathway inhibition

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Abstract Genetic aberrations in PTEN, the negative regulator of phosphoinositide 3-kinase (PI3K) signaling, are common in prostate cancers (PCA) with high Gleason Scores and correlate with adverse outcome. Currently, PI3K inhibitors, as single agents and in combination, have entered Phase I and II clinical trials for metastatic castrate resistant PCA. Alpha-specific and pan-PI3K inhibitors cause hyperglycemia as an on-target side effect by blocking insulin-dependent PI3K signaling in the liver and muscle and patients develop hyperinsulinemia in response to hyperglycemia, and insulin treatment is often needed to manage drug-induced hyperglycemia. Using human and murine prostate cancer cell lines, we examined the effect of adding insulin to BKM120 treatment on PI3K pathway activation. Using human prostate cancer cell lines LNCaP and PC3 which both express insulin receptor (IR) and IGF-1 receptor (IGF-1R), we found downregulation of the PI3K pathway by BKM120 treatment and upregulation of the PI3K pathway by insulin treatment, as assessed by AKT phosphorylation. In both cell lines, the PI3K pathway is reactivated when insulin is added to BKM120 treatment. Using cells derived from PTEN-/-P53-/- murine PCA which express low levels of IR and IGF-1R, we found minimal activation of the PI3K pathway with insulin, either alone or in combination with BKM120. Conversely, using cells derived from Myc-overexpressing mice which express high levels of IR and IGF-1R, we found robust activation of the PI3K pathway with insulin treatment. More importantly, while BKM120 abolished PI3K activity in the Myc-overexpressing cells, the addition of insulin to BKM120 resulted in the reactivation of the PI3K pathway to the level of PI3K pathway activity without BKM120 treatment. Together these findings suggest that the use of insulin in combination with BKM120 abrogates the therapeutic effect of PI3K inhibition. In addition, they indicate that PCAs that have high levels of IR and/or IGF-1 expression are particularly sensitive to PI3K inhibitors as well as insulin reactivation of the PI3K pathway. Citation Format: Lily C. Wang, Sunnie S. Kim, David M. Nanus, Lewis C. Cantley. Utilizing insulin the treatment of prostate cancer with BKM120 abrogates the therapeutic effect of PI3K pathway inhibition. [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 A33.