Abstract 2835: Potential opposing roles of AKT isoforms in indolent versus aggressive prostate cancer

Abstract

Abstract Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second highest contributor to cancer-related deaths in U.S. men. Localized CaP has a 5-year survival rate of approximately 100%, but disseminated, metastatic disease (mCaP) dramatically reduces 5-year survival to <30%. A known driving force in the progression of CaP is activation of the PI3K/Akt signaling pathway through loss of PTEN, with widespread effects on cell proliferation and migration. Additional genomic changes, such as the loss of TP53 or RB1, or the upregulation of MYC, correlate with increased incidence and aggressiveness of mCaP. However, only a fraction of men with high levels of circulating and disseminated CaP cells progress to overt, macro-metastatic disease - the lethal phenotype in CaP. Importantly, little is known regarding the drivers of indolent vs. aggressive mCaP. We used two transgenic (Tg) mouse models of mCaP with clinically relevant genetic alterations which exhibit Akt activation and Rb1 loss, yet one produces indolent mCaP and the other, systemic aggressive mCaP. Specifically, mice lacking Rb1 and the metastasis-suppressor, SSeCKS/Akap12, develop high-grade prostatic intraepithelial neoplasia (HG-PIN) and disseminated disease in the lymph nodes whereas those lacking Pten and Rb1 develop CaP and aggressive mCaP. The metastasis-suppressing functions of Akap12 relates to its ability to scaffold Src and PKC, thereby attenuating their oncogenic signaling pathways. We will show data suggesting that the pathological differences between these two Tg models is based on the differential use of PI3K-p110 and Akt isoforms, with aggressiveness correlating with the downregulation of Smad4, a known metastasis-suppressor in Tg CaP models. Additionally, differences in Akt isoform usage likely controls the expression of neurogenesis genes that are especially upregulated in castration-recurrent CaP that fails second-line androgen receptor antagonist inhibitors such as enzalutamide. By comparing the differential transcriptomes and signaling networks in primary-site tumors, lymph node metastases, and CaP cell lines derived from these two Tg models, several new potential therapeutic targets have been identified that could be exploited to prevent or treat aggressive mCaP. Citation Format: Karina A. Miller, Hyun-Kyung Ko, Irwin H. Gelman. Potential opposing roles of AKT isoforms in indolent versus aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2017-2835