KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. In this study, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid (FA) oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and FA oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled FA oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacologic inhibition of FA oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that FA oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC. SIGNIFICANCE: Treating pancreatic cancer with inhibitors that target the KRAS pathway rewires metabolism by increasing lipophagy and fatty acid oxidation, which can be targeted to sensitize tumors to KRAS signaling inhibition. See related commentary by Delgado Herrera and Ferrer, p. 3374.