Abstract A112: Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

Abstract

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need for new treatment strategies. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that sustained autophagy depletion causes a robust increase in sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil. We uncovered metabolic adaptations underlying these effects showing that chronic autophagy depletion induces metabolic rewiring to sustain nucleotides pools. Cells adapting to autophagy inhibition alter their pyruvate metabolism as a consequence of sustained mitochondrial damage. Critical rate limiting enzymes within the de novo synthesis pathway are decreased following chronic autophagy inhibition and mitochondria impairment, forcing cells to increase pyrimidine salvage instead, resulting in increased salvage of pyrimidine analogues. Based on this mechanistic understanding, we identify new and effective combinations with pyrimidine analogs and autophagy inhibitors including robust autophagy inhibitors that target the ULK1/2 kinases. These studies define how autophagy inhibition can be leveraged to treat PDA.