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=