Preclinical evaluation of a novel hyperbolic NAMPT inhibitor in combination with pan-RAS targeted therapies in pancreatic ductal adenocarcinoma
Presenter: Husain Khan, PhD Session: Novel Antitumor Agents 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Husain Yar Khan 1 , Mohammed Najeeb Al Hallak 1 , Sahar F. Bannoura 1 , Md. Hafiz Uddin 1 , Bin Bao 1 , Mohamad Walid Sukkari 1 , Adeeb Aboukameel 1 , Khalil Choucair 1 , Hugo Jimenez 1 , Grayson Barker 1 , Callum McGrath 1 , Ganji Purnachandra Nagaraju 2 , Rafic Beydoun 1 , Yang Shi 1 , Philip A. Philip 3 , Azeddine Atfi 1 , Bassel El-Rayes 2 , Ramzi M. Mohammad 1 , Min Wu 4 , Michael Schelle 4 , Boris C. Pasche 1 , Asfar S. Azmi 1 1 Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, 2 University of Alabama at Birmingham, O’Neill Comprehensive Cancer Center, Birmingham, AL, 3 Henry Ford Cancer Institute - Henry Ford Health System, Detroit, MI, 4 Remedy Plan Therapeutics, Gaithersburg, MD
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 (CI 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”.
Disclosure
H. Y. Khan, None.. M. Al Hallak, None.. S. F. Bannoura, None.. M. Uddin, None.. B. Bao, None.. M. Sukkari, None.. A. Aboukameel, None.. K. Choucair, None.. H. Jimenez, None.. G. Barker, None.. C. McGrath, None.. G. Nagaraju, None.. R. Beydoun, None.. Y. Shi, None. P. A. Philip, Bayer ), Other, Honoraria. Ipsen ), Other, Honoraria, Advisory role. Incyte ), Other, Honoraria. Taiho Pharmaceuticals ), Other, Honoraria, Advisory role. Merck ), Other, Advisory role. Astellas Pharma Other, Honoraria. BioNTech SE ), Other, Honoraria. Novartis ). Daiichi Sankyo Other, Advisory role. Celgene Other, Advisory role. Regeneron ). Genentech ). Novocure Other, Honoraria. TriSalus Life Sciences Other, Honoraria, Advisory role. SERVIER Other, Honoraria. Seagen Other, Honoraria. Halozyme ). Lilly ). SynCoreBio Other, Advisory role. Merus ). A. Atfi, None. B. El-Rayes, Pfizer ), Other, Advisory role. Taiho Pharmaceutical ). Bristol Myers Squibb ). Boston Biomedical ). Novartis ). Hoosier Cancer Research Network ). Five Prime Therapeutics ). Merck ). ICON Clinical Research ). AstraZeneca/MedImmune ). Xencor ). Bayer ). Adaptimmune ). Novartis ). IQVIA ). Zymeworks ). Covance ). Boehringer Ingelheim ). R. M. Mohammad, None. M. Wu, Remedy Plan Therapeutics Employment, Stock Option. M. Schelle, Remedy Plan Therapeutics Employment, Stock Option. Acrigen Biosciences Stock Option. B. C. Pasche, Merck ). Roche ). AstraZeneca ). Bristol Myers Squibb ). TheraBionic Inc Stock. TheraBionic GmbH Stock. A. S. Azmi, Guidepoint Inc. Other, Advisory role. Gerson Lehrman Group Other, Advisory role. Purple Biotech ). FanWave ). Colorado chromatography ). Blackstone Therapeutics ).
Cited in
Control: 3026 · Presentation Id: 8820 · Meeting 21436