PO.ET09.07 · 实验与分子治疗

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

海报缩略图：Preclinical evaluation of a novel hyperbolic NAMPT inhibitor in combination with pan-RAS targeted therapies in pancreatic ductal adenocarcinoma

编号 4579 展板 22 时间 4/21 09:00–12:00 区域 Section 17 主讲 Husain Khan, PhD

分会场 Novel Antitumor Agents 2

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作者与单位

Husain Yar Khan¹, Mohammed Najeeb Al Hallak¹, Sahar F. Bannoura¹, Md. Hafiz Uddin¹, Bin Bao¹, Mohamad Walid Sukkari¹, Adeeb Aboukameel¹, Khalil Choucair¹, Hugo Jimenez¹, Grayson Barker¹, Callum McGrath¹, Ganji Purnachandra Nagaraju², Rafic Beydoun¹, Yang Shi¹, Philip A. Philip³, Azeddine Atfi¹, Bassel El-Rayes², Ramzi M. Mohammad¹, Min Wu⁴, Michael Schelle⁴, Boris C. Pasche¹, Asfar S. Azmi¹

¹Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI,²University of Alabama at Birmingham, O’Neill Comprehensive Cancer Center, Birmingham, AL,³Henry Ford Cancer Institute - Henry Ford Health System, Detroit, MI,⁴Remedy Plan Therapeutics, Gaithersburg, MD

摘要 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<1) 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".

利益披露 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 ).

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