Abstract 1575: Immune implications of dual PIKfyve and KRAS inhibition in pancreatic ductal adenocarcinoma

Abstract Background Pancreatic Ductal Adenocarcinoma remains one of the deadliest cancers, with an overall 5 year survival rate of 13 percent. The majority of PDAC cases are driven by mutations in KRAS, making it a critical therapeutic target. Although many KRAS inhibitors have been developed and show promise in preclinical and clinical settings as single agents, the emergence of resistance and adaptive mechanisms has highlighted the need for combinatorial therapies. We recently demonstrated that the concurrent targeting of KRAS-MAPK and the lipid kinase PIKfyve disrupts lipid homeostasis in PDAC and has potent antitumor effects, curing the majority of mice in a syngeneic orthotopic mouse model. Interestingly, PIKfyve and KRAS-MAPK inhibition independently increase MHC Class 1 surface expression and enhance effectiveness of anti-PD-1 therapy. Thus, building on these findings, we hypothesized that dual inhibition of PIKfyve and KRAS-MAPK signaling modulates the immune landscape of PDAC. Methods Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1575.