Abstract P5-20-02: PTEN status dictates the roles of PI3K isoforms p110α and p110β in modulation of AKT/mTOR and response to growth factor signaling in ER+ breast cancer

Class 1A phosphatidylinositol 3-kinases (PI3Ks) regulate cell growth, survival, and metabolism. PI3Ks are heterodimeric lipid kinases composed of a p85 regulatory subunit and a p110 catalytic subunit (p110α, p110β, or p110δ). p110α and p110β play distinct roles in PI3K signaling in carcinoma cells. p110α is frequently activated by growth factor receptor kinase signaling. In contrast, p110β was shown to play a role in insulin metabolic action, G protein-coupled receptor (GPCR) and Rac1 signal transduction, and oncogenic transformation. Cancer cells deficient in PTEN, the tumor suppressor phosphatase that antagonizes PI3K signaling, are often sensitized to pharmacological inhibitors of p110β. As a result, early clinical studies with p110β inhibitors are often restricted to patients with PTEN-deficient cancers. However, analysis of data from the Genomics of Drug Sensitivity in Cancer database revealed that genetic lesions in PTEN or PIK3CA (encodes p110α) were significantly and independently associated with increased sensitivity to the p110β inhibitor AZD6284. Among 668 cancer cell lines evaluated, 61 lines had AZD6482 IC50 values ≤2 mM, but only 25 lines harbored an alteration in PTEN and/or PIK3CA. Thus, a significant fraction of cancer cell lines (and tumors) without PTEN/PIK3CA alterations are likely to be sensitive to p110β inhibition. To explore the role of p110β in PI3K signaling in ER+ PTEN-deficient breast cancer, we treated cells with the p110β inhibitor GSK2636771 and the p110α inhibitor BYL-719, alone or in combination, and assessed effects on steady state and growth factor-induced activation of AKT and MEK/ERK activation, and cell growth. p110β inhibition reduced the viability of PTEN-deficient cells; however, combined inhibition of p110α and p110β was more effective at reducing AKT and ERK phosphorylation and increasing apoptosis in ER+ PTEN-deficient cells. Furthermore, anti-estrogen treatment potentiated the anti-proliferative effects of PI3K inhibition. p110β inhibition reduced insulin-like growth factor 1 (IGF-1)-induced pAKT levels, and delayed AKT phosphorylation in both PTEN-deficient and PTEN-wild-type cells. In contrast, p110β inhibition sensitized both PTEN-wild-type and PTEN-deficient cells to heregulin stimulation, and promoted PI3K (p85)/HER3 interaction. These results indicate that p110β inhibition desensitizes cells to IGF-1 stimulation, hypersensitizes cells to heregulin, and modulates downstream AKT and MEK/ERK activation in response to growth factor receptor activation. Our findings suggest that the anti-tumor efficacy of p110β inhibitors may be related to growth factor dependence and PTEN status. Citation Format: Lloye M Dillon, Stephanie J Bouley, Todd W Miller. PTEN status dictates the roles of PI3K isoforms p110α and p110β in modulation of AKT/mTOR and response to growth factor signaling in ER+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-20-02.