Studies from us and others showed that mice with cardiomyocyte-specific overexpression of a dominant negative PI3Kp110α had smaller hearts but maintained normal cardiac function. Yet, these mice developed systolic heart failure in the presence of cardiac stress, such as chemotherapy drug doxorubicin and aortic stenosis. Currently, drugs targeting the PI3K pathway are being tested in clinical trials for cancer therapy. Therefore, it is important to assess the cardiac effects of pharmacological inhibition of this pathway. Here, we report that a dual PI3K-mTOR inhibitor, BEZ235 (BEZ), induced cardiac hypertrophy and subsequent heart failure in mice when it was used alone or in combination with doxorubicin. This effect of BEZ was associated with increased hepatic gluconeogenesis, hyperglycemia, hyperinsulinemia and increased activation of the IGFR/insulin receptor (IR) in the heart. In isolated cardiomyocyte culture, BEZ induced feedback activation of IGFR/IR, but this effect was negligible compared to the IGFR/IR activation in the presence of insulin. Injections of insulin in mice lowered blood glucose, improved glucose and pyruvate tolerance but further increased the activation of IGFR/IR in the heart and aggravated BEZ-induced cardiac dysfunction; whereas OSI-906, an IGFR/IR inhibitor, alleviated this cardiac dysfunction. In addition, low dose Metformin significantly prolonged survival and improved cardiac function in BEZ-treated mice. Taken together, these results identified hyperinsulinemia, a systematic effect of the drug, as one of the mechanisms of BEZ-induced cardiac hypertrophy, arguing animal studies are indispensable for evaluating drug toxicity. They also suggest that Metformin but not insulin should be considered for controlling hyperglycemia and preventing the cardiac side effects that may be caused by PI3K pathway inhibitors in clinic.

Citation Format: Jillian Onufrak, Yongayo Yang, Juyong Lee, John Fuseler, Maoyun Sun, Sharath Sasi, J. Tyson McDonald, Lynn Hlatky, Robert L. Price, Joseph Carrozza, David Goukassian, Thomas K. Borg, James P. Morgan, Xinhua Yan. A dual PI3K-mTOR inhibitor induced cardiac hypertrophy in mice: Role of the insulin signaling. [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 A56.