Abstract A25: Activating alterations of p110 subunits determine PI3K isoform selectivity in prostate cancer

Abstract

Abstract Oncogenic activity of PI3K mutated tumors is often dependent on different PI3K isoforms. In breast cancer PI3Kα activating mutations are dominant drivers, whereas in PTEN-deficient prostate cancer such activity is thought to be driven by PI3Kβ. In particular, loss of PTEN function is seen in 40% of metastatic prostate cancer patients, which remains a challenging clinical problem. Recent success of selectively targeting PI3Kα or PI3Kβ to treat disease caused by hyperactivation of PI3K pathway sheds light on further developing such agents to a boarder disease spectrum. Yet relatively little is known about how different PI3K isoforms are selected as dominant drivers in different genetic and pathologic contexts. Here we use multiple prostate cancer cell lines and organoid models to study the mechanisms of PI3K isoform dependency in prostate cancer. We found PI3K isoform dependency is not always correlated with PTEN status across a panel of prostate cancer models in which different levels of PI3K signaling are observed. However, such dependency can be shifted towards either PI3Kα or PI3Kβ in the presence of its corresponding activating alteration, regardless of its original isoform dependency. Interestingly, such PI3K isoform activating alteration is able to further enhance PI3K signal in the setting of PTEN loss. PI3Kα mutant models are more sensitive to the α selective inhibitor BYL719 while PI3Kβ mutant models are more sensitive to the β selective inhibitor AZD8186. Besides, we found that PI3Kα mutant prostate tumors are sensitive to PI3Ksy inhibition by AZD8186 at a high dosage both in vitro and in vivo. High dose of AZD8186 also inhibits PI3K signaling in PI3Kα mutant breast cancer models. These data raise the possibility that the PI3Kβ selective inhibitor AZD8186 can also target PI3Kα at a high dose. In an ongoing clinical trial at MSK, a prostate cancer patient with PI3Kα mutation also responded to PI3Kβ inhibition. This finding reveals a new mechanism of how PI3K activating mutations determine PI3K isoform selectivity regardless of PTEN status. Results from this study also present new opportunities to treat cancer patients with PI3Kα or PI3Kβ inhibition. Citation Format: Zeda Zhang, Ninghui Mao, Young Sun Lee, Dan Li, Neal Rosen, Charles Sawyers, Brett Carver. Activating alterations of p110 subunits determine PI3K isoform selectivity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A25.