Abstract 2649: Inhibition of mTOR, but not PI3K, is required for the anti-tumor efficacy in breast cancer of dual PI3K/mTOR inhibitors given in combination with MEK inhibitors

Abstract

Background: The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are deregulated in many cancers including breast cancer. Additionally, studies have shown that significant crosstalk exists between these pathways; often making single pathway inhibition ineffective. While, combined PI3K/mTOR and MEK inhibition appears highly active in pre-clinical models, the combination has been reported to be toxic in human use. In an effort to produce a more targeted regimen, we examined whether both PI3K and mTOR inhibition are required for pre-clinical anti-tumor efficacy in combination with a MEK inhibitor. Methods: In vivo studies assessed overall survival and best tumor response upon administration of dual PI3K/mTOR (BEZ235 and GSK806) versus allosteric mTOR inhibition (Everolimus) in combination with MEK inhibition (AZD244 and GSK212) in genetically engineered murine models (GEMM) of breast cancer [T11 and C(3)Tag]. Activation and response of the PI3K/mTOR and MEK/ERK pathways to dual PI3K/mTOR, allosteric mTOR inhibition, and MEK inhibition were assessed in vitro in murine cell lines derived from the above GEM models. Results: Single agent regimens of MEK, allosteric mTOR, or dual PI3K/mTOR inhibition were minimally effective in C(3)Tag or T11 tumors in vivo. As previously reported, combined PI3K/mTOR and MEK inhibition showed potent pre-clinical activity in both the T11 and C3Tag models, prolonging overall survival relative to both vehicle or single-agent treated mice. Surprisingly, combinations of MEK inhibitors with allosteric mTOR inhibitors were as active as the MEK/PI3K/mTOR combination. In vitro studies in cell lines derived from these tumor models showed that mTORC1 inhibition, but not PI3K inhibition, resulted in compensatory activation of MEK. Conclusions: Combined targeting of the mTOR and MEK pathways results in improved response and survival in faithful GEM models of breast cancer. The combination of dual PI3K/mTOR catalytic inhibitors with MEK inhibition does not afford benefit over combined allosteric mTOR and MEK inhibition Citation Format: Aleisha M. Smith, Jessie Xiong, Lucas Hunter, Jamie Jordan, Kelly Clark, David B. Darr, Sharpless Norman, Charles M. Perou, William Y. Kim. Inhibition of mTOR, but not PI3K, is required for the anti-tumor efficacy in breast cancer of dual PI3K/mTOR inhibitors given in combination with MEK inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2649. doi:10.1158/1538-7445.AM2015-2649