Oncogenic and epigenetic inhibitors kill castration-resistant prostate cancer by cooperatively suppressing energy metabolism

Abstract

Prostate cancer is the second leading cause of cancer-related deaths in men. Most patients diagnosed with advanced prostate cancer develop resistance to first-line treatments, and eventually develop incurable castration-resistant prostate cancer (CRPC). Thus, there is an unmet clinical need to develop more effective therapies for this disease. This dissertation presents co-targeting the oncogenic PI3K/AKT signaling pathway and the epigenetic regulator EZH2 as an effective combinatorial strategy to kill castration-resistant prostate cancer in pre-clinical models. The PI3K signaling pathway in overactive in 70% of CRPC tumors, and defects in the pathway are linked to disease progression. EZH2 is also overexpressed in metastatic prostate cancer, correlates with lower failure-free survival, and has been shown to induce metastasis in mouse models of prostate cancer. In my dissertation, we demonstrate that EZH2 inhibitor synergizes with multiple PI3K signaling pathway inhibitors to kill CRPC in vitro, and causes tumor regression in vivo. Unbiased transcriptional and metabolic approaches revealed that EZH2 and PI3K/AKT signaling inhibitors kill CRPC by cooperatively suppressing glycolysis and oxidative phosphorylation, causing devastating energy crisis. Additional mechanistic and functional studies demonstrated that PI3K pathway and EZH2 inhibitors cooperatively suppress these metabolic pathways by dramatically decreasing the critical metabolic regulators HIF-1A and MYC at the protein level. In parallel, EZH2 inhibition upregulates the pro-apoptotic sensor protein BMF, which triggers apoptosis in response to the metabolic stress. Additionally, I also discuss some preliminary positive and negative results aimed at elucidating the mechanism by which EZH2 inhibitors suppress MYC expression and metabolism. Specifically, I propose that EZH2 inhibition leads to a feedforward loop between decreased MYC translation and amino acid transport. Moreover, I report a list of direct EZH2 targets in CRPC, which includes FOXO1 and FOXO3 as potential critical regulators of cell death in response to EZH2 and PI3K pathway inhibitors. Together, the data presented in this dissertation reveals a promising therapeutic strategy for CRPC, and demonstrates how energy metabolism can be fatally suppressed by targeting upstream oncogenic and epigenetic nodes.