Abstract B28: Activating mutations in PIK3CB confer resistance to PI3K inhibition in PTEN-deficient breast cancer and define a novel oncogenic role for p110β

Abstract

Abstract Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs commonly in breast cancers via mechanisms that include loss of function of the tumor suppressor phosphatase and tensin homolog (PTEN). Experience with other successful targeted agents suggests that clinical resistance to PI3K inhibitors is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN deficient breast cancers. PTEN null breast cancer cell lines were selected for resistance to a pan-PI3K inhibitor, GDC-0941. Comprehensive molecular and cellular profiling was conducted to identify the mechanism of resistance. We generated GDC-0941 resistant derivatives of PTEN deficient EVSA-T and ZR-75-1 cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines. We found that the PIK3CB mutation at D1067 position was recurrent in cancer patients. Stable expression of mutant PIK3CB variants in PTEN null breast cancer cells conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. We showed further that the p110β D1067Y mutant is highly activated and elevates PIP3 level at the cell membrane, promoting localization and activation of AKT and PDK1 at the cell membrane and driving PI3K signaling to a level that can overcome treatment with proximal inhibitors. Finally, we show that the PIK3CB D1067Y mutant can behave as an oncogene and transform normal cells, and that PTEN knock down enhances this activity. These novel preclinical and clinical findings implicate PIK3CB D1067 alterations as a novel oncogene that may cause resistance to selective PI3K inhibitor treatment. Taken together with previous findings that PTEN deficient cancers tend to signal through p110β rather than p110α, this work also suggests PTEN deficient breast cancers may depend on p110β and are thereby susceptible to PIK3CB mutation as an escape mechanism from PI3K inhibition. Citation Format: Yoshito Nakanishi, Kimberly M. Walter, Jill M. Spoerke, Carol O'Brien, Ling Y. Huw, Garret M. Hampton, Mark R. Lackner. Activating mutations in PIK3CB confer resistance to PI3K inhibition in PTEN-deficient breast cancer and define a novel oncogenic role for p110β. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B28.