Abstract 6764: Lipophagy-dependent fatty acid oxidation is a metabolic vulnerability for KRAS signaling inhibition in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by activating mutations in KRAS, which promote tumor progression through sustained activation of the MAPK (RAS/RAF/MEK/ERK) signaling pathway. This study investigates the metabolic vulnerabilities associated with PDAC by examining the metabolic reprogramming that occurs upon KRAS signaling inhibition via targeting MEK/ERK/KRASG12D, and utilizing metabolomic, lipidomic, and isotope-tracing approaches. Our findings reveal that MEK/ERK/KRASG12D inhibition results in enhanced lipid turnover and fatty acid oxidation while suppressing glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Notably, we observed that the increased lipid turnover and fatty acid oxidation are mediated by lipophagy, rather than cytosolic lipolysis. Furthermore, these processes are driven by enhanced nuclear translocation and transcriptional activity of TFEB, a key regulator of lysosomal biogenesis and autophagy. Pharmacological inhibition of fatty acid oxidation, when combined with MEK/ERK/KRASG12D inhibitors, exhibited synergistic anti-tumor effects, significantly reducing the growth of PDAC cell lines and organoids. This combination therapy also decreased tumor burden and improved overall survival in orthotopic cell line-derived 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, offering a promising therapeutic target to enhance the efficacy of KRAS pathway inhibitors. Citation Format: Junzhang Zhao, Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Surendra K. Shukla, Kirsten L. Bryant, Kamiya Mehla, Channing J. Der, Pankaj K. Singh. Lipophagy-dependent fatty acid oxidation is a metabolic vulnerability for KRAS signaling inhibition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6764.