Abstract LB056: Metabolic adaptations under high glucose enhance lipid synthesis inhibitor efficacy in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for over 90% of cases. Despite advances in treatment, the 5-year survival rate is less than 13% in the United States. The majority of PDAC cases do not display any symptoms and are diagnosed in the late stage, where Chemotherapies like gemcitabine or FOLFIRINOX offer limited benefits. Resistance to these treatments further underscores the need for novel strategies. Recently, lipid metabolism has emerged as a promising target for PDAC therapy. However, monotherapies targeting lipid synthesis pathways have shown limited efficacy. In the current study, we have presented a feasible and effective strategy to improve the therapeutic impact of lipid synthesis inhibitors. We demonstrated that high glucose conditions induce metabolic rewiring in PDAC cells, elevating the expression of lipid synthesizing enzymes, including Fatty Acid Synthase (FASN), ATP citrate lyase (ACLY), HMG-CoA reductase (HMGCR), and Stearoyl-CoA desaturase (SCD). This metabolic shift increases cancer cells dependency on lipid synthesis for survival and proliferation Furthermore, high glucose level inhibited nuclear enrichment of IDH1 protein whereas low glucose promoted nuclear enrichment of IDH1 in PDAC cells. We hypothesized that loss of nuclear IDH1 during high glucose condition may reprogram the chromatin states by modulating epigenetic marks. Our study showed that high glucose condition enhances histone acetylation (H3K9Ac, H3K14Ac) and methylation (H3K4Me3, H3K4Me and H3K36Me2) favoring transcriptional upregulation of lipid synthesizing genes. Additionally, high glucose activated mTOR and NADK that promote lipid biosynthesis. To assess therapeutic potential, we treated PDAC cell lines (PANC-1, BxPC3, and KPC8484) with FASN inhibitor TVB-2023 under low and high glucose conditions. Interestingly, high glucose significantly enhanced the efficacy of FASN inhibitor in in vitro model. In conclusion, our findings reveal that the hyperglycemic state drives a metabolic shift in PDAC cells depending on lipid synthesis pathway resulting sensitization to lipid synthesis inhibitors. Citation Format: Goutam Dey, Mehrdad Zarei, Omid Hajihassani, Priyashree Sunita, Hallie J Graor, Faith Nakazzi, Jordan M. Winter. Metabolic adaptations under high glucose enhance lipid synthesis inhibitor efficacy 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 LB056.