Abstract 1871: Combined RAS and ICB inhibition targets NF-KB-driven immune evasion in chemoresistant pancreatic cancer.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with surgery as the only potentially curative option. However, 85% of patients present with inoperable disease. For these patients, chemotherapy remains the standard treatment, though nearly all develop resistance and disease progression. We hypothesize that resistance to chemotherapy and RAS inhibitors reshapes the tumor microenvironment (TME), and understanding these changes is key to developing effective combination therapies. To investigate resistance mechanisms, we generated chemoresistant (CR) PDAC models. Parental (PT) and CR cells were orthotopically implanted into syngeneic mice and treated with vehicle or MRTX1133. The TME was analyzed using flow cytometry, single-cell RNA sequencing (scRNA-seq), multiplex immunohistochemistry, and immunofluorescence. RNA sequencing and cytokine arrays characterized cancer-TME crosstalk. NF-κB signaling was interrogated for its effects on cytokine and immune checkpoint expression. In addition, human PDAC organotypic slice cultures were treated with RMC6236 and immune checkpoint blockade (ICB). In vivo experiments tested MRTX1133 in combination with anti-CTLA-4 or dual anti-CTLA-4 + anti-PD1 therapy. RNA-seq revealed significant KRAS pathway upregulation in CR tumors and NF-κB pathways in RASi-treated tumors. MRTX1133 treatment of CR tumors significantly reduced tumor volumes and weights compared to vehicle controls and PT tumors (P=<0.01). Histological and scRNA-seq analyses demonstrated that CR tumors had expanded epithelial and fibroblast compartments and decreased T cell and macrophage populations, which were rescued by MRTX1133 treatment (P=<0.001). Cytokine profiling showed that CR tumors treated with MRTX1133 exhibited increased CXCL10 and CCL2, and decreased GM-CSF and LIF. NF-κB signaling regulated expression of CCL2, GM-CSF, and LIF, and also influenced immune checkpoint expression in T cells, linking tumor-intrinsic signaling with T cell exhaustion pathways. Human PDAC organotypic slice cultures treated with anti-CTLA-4 antibody showed reduced epithelial cell populations compared to controls, suggesting improved therapeutic response. In vivo, MRTX1133 combined with anti-CTLA-4 and anti-PD1 antibodies significantly reduced tumor volumes and prolonged survival compared to MRTX1133 and anti-CTLA-4 or monotherapy with MRTX1133. KRAS inhibition controls tumor growth in chemorefractory PDAC and improves immune infiltration. Mechanistically, RASi in tumor cells activate NF-κB signaling, driving cytokine changes that enhance PD-1 and CTLA-4 expression in T cells. Targeting these NF-κB-driven cytokines and immune checkpoints alongside RAS inhibition represents a promising combinatorial strategy to overcome chemoresistance and improve PDAC outcomes. Citation Format: Kevin Christian Gulay, Alexei Martsinkovskiy, Isabella Ng, Deepa Sheik Pran Babu, Jay Patel, Rithika Medari, Ponmathi Panneerpandian, Tatiana Hurtado de Mendoza, Andrew Lowy, Herve Tiriac. Combined RAS and ICB inhibition targets NF-KB-driven immune evasion in chemoresistant pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1871.