Abstract A019: Enhancing RAS therapies by targeting PIKfyve in pancreatic cancer

Abstract BACKGROUND: RAS inhibitors are reshaping the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC), with both mutant-specific and pan-RAS agents demonstrating unprecedented efficacy across treatment lines. Nevertheless, relapse remains universal, underscoring the need for durable combination strategies. We recently demonstrated the lipid kinase PIKfyve as a therapeutic vulnerability in PDAC. Notably, inhibitors of PIKfyve (ESK981, apilimod) markedly enhanced the activity of MEK inhibitors (selumetinib and trametinib) and the KRASG12D-selective inhibitor MRTX1133. In patient-derived xenografts, trametinib plus ESK981 induced near-uniform and sustained tumor regressions, and in multiple immunocompetent models, this combination eliminated detectable tumor burden. Despite this, tumors eventually recurred, indicating survival of a rare drug-persistent population. METHODS AND RESULTS: Using syngeneic orthotopic PDAC models, we now aim to 1) evaluate whether the PIKfyve inhibitor ESK981 can similarly potentiate the clinical pan-RAS inhibitor RMC-6236 and 2) identify strategies to sustain complete regressions. Thus far, RMC-6236 plus ESK981 is well tolerated and induces complete responses in a subset of mice. However, after therapy withdrawal, all tumors regrew and animals ultimately succumbed within 2 months, mirroring our prior observations. FUTURE DIRECTIONS: These results suggest that a minimal reservoir of drug-persistent cells survives dual RAS/PIKfyve inhibition and seeds recurrence. Because both RAS inhibition and PIKfyve blockade independently upregulate MHC-I and PD-L1 expression, we hypothesize that adding immune checkpoint blockade may leverage adaptive anti-tumor immunity to eradicate residual disease. Ongoing studies are testing this triple-therapy approach as a route to durable cures. No AI was used in the conduct of any part of this study. AI was used to revise the abstract that the presenting author drafted. The presenting author subsequently reviewed, revised, and edited the draft prior to submission. Citation Format: Caleb Cheng, Jasmine P. Wisniewski, Yuanyuan Qiao, Costas A. Lyssiotis, Arul M. Chinnaiyan. Enhancing RAS therapies by targeting PIKfyve in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A019.