Abstract B048: Metabolic adaptations under high glucose enhance KRAS and 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. In the current study, we have presented a feasible and effective strategy to improve the therapeutic impact of KRAS and lipid synthesis inhibitors. We showed that high glucose treatment in PDAC cells drives the methionine cycle and increases the expression of DOT1L. DOT1L is known to methylate histone H3 at lysine 79, a modification involved in active transcription. We further demonstrated that pharmacological inhibition of DOT1L suppresses KRAS expression. In parallel, we showed that high-glucose conditions induce metabolic rewiring in PDAC cells, elevating the expression of KRAS and 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' dependence on KRAS and on lipid synthesis for survival and proliferation. To assess therapeutic potential, we treated PDAC cell lines with KRAS G12D inhibitor (MRTX1133) and FASN inhibitor TVB-2023 under low- and high-glucose conditions. Interestingly, high glucose significantly enhanced the efficacy of KRAS and FASN inhibitors in an in vitro model. In conclusion, our findings reveal that the hyperglycemic state drives a metabolic shift in PDAC cells depending on the KRAS and lipid synthesis pathways, resulting in sensitization to KRAS and lipid synthesis inhibitors.