Abstract A85: Metabolic wiring dictates GOT1 dependency in pancreatic cancer

Abstract

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is an extremely aggressive disease. The 5-year survival rate is a shockingly low 8%, a number that has hardly increased in the last 30 years. This owes in large part to the fact that effective treatment options for PDA do not exist. A hallmark of pancreatic cancers, and one that contributes to this resistance, is the metabolic environments that they create locally and systemically. Pancreatic tumors exist in a highly inflammatory environment, are under severe physical and oxidative stress, and do not have functional vasculature to deliver oxygen and nutrients. Despite these unfavorable circumstances for growth, these tumors thrive. Clearly metabolism is rewired in unique ways to facilitate survival and growth in this unusual and hostile environment. Based on this framework, we have been mapping the metabolic pathways in PDA to identify aspects of metabolism that are unique or highly over-utilized. Previously, we defined a novel pathway used by PDA cells to maintain redox balance via NADPH generation. Inhibition of a central enzyme in this pathway, cytosolic aspartate aminotransferase (GOT1), dramatically impairs growth in vitro and in vivo. Importantly, these effects can be completely reversed by supplying PDA cells with antioxidants. We also found that this pathway is regulated by mutant KRAS in PDA and, accordingly, non-transformed pancreatic epithelial cells are unresponsive to GOT1 inhibition. Subsequently, we interrogated GOT1 dependence in another KRAS transformed cancer, colon cancer, and found that they, like non-transformed cells, do not respond to GOT1 inhibition. Through a detailed series of metabolomics and functional assays, we ultimately found that colon cancers bypass GOT1 dependence favoring flux through ATP citrate lyase (ACL), a mechanism dictated not at the transcriptional level but by the metabolic wiring in these cells. Furthermore, ACL knockdown dramatically sensitizes colon cancer cells to GOT1 inhibition mediated redox and growth defects. In addition to revealing novel aspects of tissue specific metabolic pathway regulation, this analysis also illustrated novel metabolic dependencies that can be exploited for therapeutic gain. Citation Format: Costas A. Lyssiotis.{Authors}. Metabolic wiring dictates GOT1 dependency in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A85.