Abstract A023: Combined RAS and ICB inhibition targets NF-κB–driven immune evasion in chemoresistant pancreatic cancer

Abstract Introduction Chemotherapy remains the standard treatment for most pancreatic ductal adenocarcinoma (PDAC) patients, though nearly all develop resistance. Clinical trials exploring Ras inhibitors (RASi) in chemotherapy-refractory patients are underway, yet emerging data suggest resistance will develop. We hypothesize that chemoresistant (CR) reshapes the tumor microenvironment (TME), and understanding these changes is key to developing effective Ras combination therapies for chemorefractory patients. Methods To investigate resistance mechanisms, we generated CR 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 (IHC), and immunofluorescence (IF). RNA sequencing and cytokine arrays characterized cancer to TME crosstalk. NF-κB signaling was interrogated for its effects on cytokine and immune checkpoint expression. 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 and anti-PD1 therapy. Results RNA-seq revealed significant KRAS pathway upregulation in CR tumors. NF-κB pathway was upregulated in RASi-treated tumors. MRTX1133 treatment of CR tumors significantly reduced tumor volumes compared to vehicle controls and PT tumors (P=0. 01). IHC/IF/scRNA-seq demonstrated that CR tumors had expanded epithelial and fibroblast compartments and decreased T cell and macrophage populations. This was reversed with MRTX1133 treatment (P=0. 001). Cytokine profiling showed that CR tumors treated with MRTX1133 exhibited increased CCL2. Mechanistically, NF-κB signaling regulated the expression of CCL2 and modulated immune checkpoint expression in T cells, establishing a link between tumor-intrinsic NF-κB activity and T cell exhaustion pathways. Human PDAC slice cultures treated with RMC6236 and ICB exhibited a reduction in epithelial tumor cell populations compared with control treatments, indicating enhanced therapeutic efficacy. In vivo, combination therapy with MRTX1133 and anti-CTLA-4 significantly reduced tumor burden compared with MRTX1133 monotherapy (P = 0. 0004) and resulted in prolonged overall survival of CR tumor-bearing mice (P = 0. 0328). Notably, in these mice, triple therapy with MRTX1133, anti-CTLA-4, and anti-PD-1 further extended survival relative to MRTX1133 plus anti-CTLA-4 treatment (P = 0. 0476). Conclusion Mechanistically, CR tumor cells treated with RASi 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 M. Gulay, Alexei Martsinkovskiy, Isabella Ng, Deepa Sheik Pran Babu, Ponmathi Panneerpandian, Jay Patel, Tatiana Hurtado de Mendoza, Andrew M. Lowy, Hervé Tiriac. Combined RAS and ICB inhibition targets NF-κB–driven immune evasion in chemoresistant 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 (5Suppl₁): Abstract nr A023.