PO.ET09.07 · 实验与分子治疗

一种新型双曲线型NAMPT抑制剂联合pan-RAS靶向疗法在胰腺导管腺癌中的临床前评估

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 Authors & Affiliations

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

中文摘要

背景：胰腺导管腺癌（PDAC）仍然是高度致命的，由近乎普遍的KRAS突变和对烟酰胺腺嘌呤二核苷酸（NAD）的深度代谢依赖所驱动。NAMPT是NAD补救途径的限速酶，在KRAS驱动的肿瘤中常上调，提示存在代谢共依赖。我们评估了同时阻断NAMPT和KRAS信号是否能增强PDAC的抗肿瘤疗效。方法：在TCGA PDAC样本（n=179）中分析了KRAS-NAMPT表达相关性。用双曲线型NAMPT抑制剂RPT-E-037、RMC6236或两者联合处理多种KRAS突变型PDAC细胞模型，包括KRASG12C抑制剂、KRASG12D抑制剂和pan-RAS抑制剂（RMC6236）耐药系。在2D活力测定、3D球体培养以及患者来源的2D/3D共培养系统中评估抗肿瘤活性。使用联合指数（CI）分析计算药物相互作用。结果：TCGA分析显示KRAS与NAMPT表达之间存在相当强的正相关（Spearman ρ=0.59）。与亲本细胞相比，RMC6236耐药PDAC细胞表现出NAMPT表达增加以及对RPT-E-037的敏感性升高。在KRASG12C和KRASG12D抑制剂耐药模型中也观察到类似的NAMPT上调和NAMPT抑制剂敏感性增强。在多种KRAS突变型PDAC系中，RPT-E-037与RMC6236联合在2D和3D培养中均产生了稳健的协同作用（CI<1）。在患者来源的PDAC共培养系统中，该联合方案比单药更有效地显著减少肿瘤体积、瓦解紧密的球体结构并破坏肿瘤-基质相互作用。KRASG12D突变型转移患者快速尸检组织来源以及KPC小鼠肿瘤来源的皮下和原位异种移植研究正在进行中。结论：双重抑制NAMPT介导的NAD生物合成和KRAS信号在PDAC（包括对KRAS靶向疗法耐药的模型）中产生协同抗肿瘤活性。这些发现支持NAMPT-KRAS共依赖作为一种可治疗干预的脆弱性，并证明有必要开展进一步的转化和体内研究，以指导临床开发和基于生物标志物的患者选择。"本摘要使用了生成式AI来改进语言"。

查看英文原文 English 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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