Abstract IA13: Identifying metabolic dependencies in pancreatic cancer

Abstract

Abstract Pancreatic cancers are highly resistant to currently available therapeutics which results in a 5-year survival rate of approximately 11%. We believe that this resistance points toward altered cell metabolic pathways. In this regard we have previously shown that that oncogenic Kras promotes a rewiring of pancreatic cancer metabolism allowing carbon sources to be utilized in a variety of biosynthetic pathways. Importantly, several of these metabolic pathways are critical for tumor growth and therefore represent potential therapeutic targets. Ongoing studies from our group are exploring targeting various aspects of metabolism as therapeutic approaches. Additional studies from our group have demonstrated pancreatic cancers have elevated basal autophagy which is required for their continued growth. Importantly, inhibition of autophagy pharmacologically or genetically leads to decreased oxidative phosphorylation, a drop in ATP production, and ultimately growth inhibition. These findings have implicated autophagy as a key component of pancreatic cancer metabolism and have motivated the opening of multiple clinical trials assessing the efficacy of hydroxychloroquine as an autophagy inhibitor in pancreatic cancer, which have now shown clinical activity in pancreatic cancer patients. Recently, we have identified a novel selective autophagy pathway that degrades MHC-I and promotes immune evasion in pancreatic tumors. Ongoing work from our group seeks to understand the metabolic contributions that autophagy makes in pancreatic tumors. These and other aspects of pancreatic cancer metabolism will be discussed. Citation Format: Alec Kimmelman. Identifying metabolic dependencies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA13.