Abstract SY13-01: Targeting the metabolic basis of resistance to Kras signaling inhibition in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma patients show poor prognosis due in part to poor response to standard-of-care therapies. Hence, there is an urgent need to identify novel therapeutic strategies. Oncogenic Kras mutations are a key driver of PDAC tumorigenesis. Novel Kras-targeted therapies have demonstrated improved efficacies in preclinical models and are currently under trial in the clinic. However, resistance has been observed against these therapies. Metabolic alterations play a key role in regulating therapy responsiveness. Notably, Krasis a key regulator of metabolic reprogramming in pancreatic cancer. Thus, we examined the metabolic reprogramming that occurs upon KRAS signaling inhibition via targeting MEK, ERK, or KRASG12D. We utilized metabolomic, lipidomic, and isotope-tracing approaches to investigate the metabolic alterations that may allow cells to escape Kras signaling inhibition. Our findings reveal that inhibition of MEK, ERK, or KRASG12Dresults in enhanced lipid turnover and fatty acid oxidation while suppressing glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. We confirmed the increased lipid turnover by kinetic flux analysis of stable-isotope-labeled palmitate that showed increased breakdown of palmitate into acetyl-CoA and the TCA cycle metabolites in cells treated with inhibitors of Kras signaling. Notably, we observed that the increased lipid turnover and fatty acid oxidation are mediated by lipophagy, rather than cytosolic lipolysis. The increased lipophagy was driven by enhanced nuclear translocation and transcriptional activity of Transcription factor EB (TFEB), a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors. TFEB regulated multiple lipid catabolism and lipophagy-related genes. Inhibiting fatty acid oxidation by genetic perturbations or by utilizing pharmacological agents exhibited synergistic anti-tumor activity when combined with MEK/ERK/KRASG12D inhibitors in pancreatic cancer cell lines and organoids. This combination therapy also decreased tumor burden and improved overall survival in orthotopic cell line injection and patient-derived xenograft (PDX) mouse models. These results provide novel mechanistic insights into the metabolic adaptations underlying resistance to Kras signaling inhibition. These studies highlight fatty acid oxidation as a critical metabolic vulnerability in PDAC upon KRAS signaling inhibition, offering a promising therapeutic target toenhance the efficacy of KRAS pathway inhibitors. The identified novel combinationspresent an opportunity to improve patient outcomes. Citation Format: Pankaj Kumar Singh. Targeting the metabolic basis of resistance to Kras signaling inhibition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY13-01.