Abstract 4579: Preclinical evaluation of a novel hyperbolic NAMPT inhibitor in combination with pan-RAS targeted therapies in pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, driven by near-universal KRAS mutations and profound metabolic dependence on nicotinamide adenine dinucleotide (NAD). NAMPT, the rate-limiting enzyme of the NAD salvage pathway, is frequently upregulated in KRAS-driven tumors, suggesting metabolic co-dependence. We evaluated whether simultaneous blockade of NAMPT and KRAS signaling enhances antitumor efficacy in PDAC. Methods: KRAS-NAMPT expression correlations were analyzed in TCGA PDAC samples (n=179). Multiple KRAS-mutant PDAC cellular models, including KRASG12C inhibitor, KRASG12D inhibitor, and pan-RAS inhibitor (RMC6236)-resistant lines were treated with the hyperbolic NAMPT inhibitor RPT-E-037, RMC6236, or both. Antitumor activity was assessed in 2D viability assays, 3D spheroid cultures, and patient-derived 2D/3D co-culture systems. Drug interactions were calculated using combination index (CI) analysis. Results: TCGA analysis revealed a fairly strong positive correlation between KRAS and NAMPT expression (Spearman ρ=0.59). RMC6236-resistant PDAC cells displayed increased NAMPT expression and heightened sensitivity to RPT-E-037 compared to parental cells. Similar NAMPT upregulation and enhanced NAMPT inhibitor sensitivity were observed in KRASG12C and KRASG12D inhibitor-resistant models. Across KRAS-mutant PDAC lines, RPT-E-037 combined with RMC6236 produced robust synergy (CI1) in both 2D and 3D cultures. In patient-derived PDAC co-culture systems, the combination significantly reduced tumor mass, dismantled compact spheroid architecture, and disrupted tumor-stroma interactions more effectively than either agent alone. KRASG12D-mutant metastatic patient rapid autopsy tissue-derived and KPC mice tumor-derived subcutaneous and orthotopic xenograft studies with the combination are ongoing. Conclusion: Dual inhibition of NAMPT-mediated NAD biosynthesis and KRAS signaling yields synergistic antitumor activity in PDAC, including models resistant to KRAS-targeted therapies. These findings support NAMPT-KRAS co-dependency as a therapeutically actionable vulnerability and justify further translational and in vivo studies to guide clinical development and biomarker-based patient selection."Generative AI was used for improving the language of the abstract". Citation Format: Husain Yar Khan, Mohammed Najeeb Al Hallak, Sahar F. Bannoura, Md. Hafiz Uddin, Bin Bao, Mohamad Walid Sukkari, Adeeb Aboukameel, Khalil Choucair, Hugo Jimenez, Grayson Barker, Callum McGrath, Ganji Purnachandra Nagaraju, Rafic Beydoun, Yang Shi, Philip A. Philip, Azeddine Atfi, Bassel El-Rayes, Ramzi M. Mohammad, Min Wu, Michael Schelle, Boris C. Pasche, Asfar S. Azmi. Preclinical evaluation of a novel hyperbolic NAMPT inhibitor in combination with pan-RAS targeted therapies in pancreatic ductal adenocarcinoma 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 4579.