Abstract B054: Combined RAS Inhibition and Immune Checkpoint Blockade Overcome NF-κB-Mediated Immune Evasion in Chemoresistant Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Surgery is the only potentially curative treatment, yet approximately 85% of patients present with unresectable disease. For these patients, chemotherapy remains the standard treatment, though nearly all develop resistance and disease progression. Recently developed RAS and KRAS inhibitors have shown promising clinical activity in PDAC, but it remains unknown whether acquired chemoresistance alters therapeutic response or promotes subsequent resistance to RAS inhibition. To address this critical knowledge gap, we evaluated responses to RAS inhibition in chemoresistant PDAC using patient-derived organoids (PDOs), isogenic chemoresistant models, orthotopic syngeneic mouse models, and human tumor ex vivo cultures. Transcriptomic and functional analyses revealed that RAS inhibition in chemoresistant tumors activates an NF-κB–driven inflammatory program that promotes T-cell infiltration while simultaneously inducing adaptive immune resistance characterized by increased PD-1 and CTLA-4 expression. We then evaluated RAS inhibition in combination with immune checkpoint blockade, which significantly improved treatment outcomes in chemoresistant tumor-bearing mice but not in chemonaïve tumor-bearing mice. Specifically, in chemoresistant PDAC, Daraxonrasib combined with dual CTLA-4 and PD-1 blockade induced marked tumor regression and significantly prolonged survival compared with Daraxonrasib alone (P=0.0094) or vehicle (P<0.001). Collectively, our results show that chemoresistant PDAC remains sensitive to RAS inhibition, but durable therapeutic benefit requires concurrent immune checkpoint blockade to counteract the NF-κB-mediated T-cell exhaustion. These findings identify NF-κB-mediated T-cell exhaustion as a mechanism limiting RAS inhibitor efficacy in chemoresistant PDAC and provide a strong rationale for combining RAS inhibition with dual immune checkpoint blockade to improve outcomes in chemotherapy-refractory PDAC.