Li Tao, Yu Xianqiang, Wan Xinyao, Liu Jing, Zheng Jie, Sun Ziyu, Zhao Yi, Chen Jiakang, Chen Hongli, Yang Yifeng, Jiang Biao
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Eur J Med Chem. 2025 Mar 15;286:117305. doi: 10.1016/j.ejmech.2025.117305. Epub 2025 Jan 20.
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with poor prognosis. Antibody-drug conjugates (ADCs) and their combinations with various anti-tumor drugs have made great progress. Camptothecin, and its derivatives (Dxd, SN-38 or exatecan) targeted TOP1 are effective payloads due to their potent anti-tumor activity. ADCs offer a promising avenue, particularly when integrated with synthetic lethality strategies. In this study, the ADC SA-7-49 is engineered by conjugating exatecan to an anti-TROP2 antibody. The synthetic lethality between camptothecin and the ataxia telangiectasia-mutated and rad3-related (ATR) inhibitors in PDAC cells has been identified through a comprehensive screening of DNA damage response pathways. Drug interactions are quantified using Zero interaction potency (ZIP) scores. RNA sequencing is employed to elucidate the mechanisms driving synergistic effects. ATR inhibitors synergize with camptothecin by inducing apoptosis via ATR-Chk1 pathway inhibition. Knockdown of ATR enhances the sensitivity of PDAC cells to camptothecin and SA-7-49. SA-7-49 selectively targets and eradicates PDAC cells and xenografts without side effects, augmenting anti-tumor activity via synthetic lethality. Our findings reveal a novel therapeutic strategy by integrating ADC technology with synthetic lethality in PDAC.
胰腺导管腺癌（PDAC）仍然是一种预后很差的高致死性恶性肿瘤。抗体药物偶联物（ADC）及其与各种抗肿瘤药物的联合应用已取得了很大进展。喜树碱及其靶向拓扑异构酶1（TOP1）的衍生物（德喜曲妥珠单抗、SN-38或依喜替康）因其强大的抗肿瘤活性而成为有效的有效载荷。ADC提供了一条有前景的途径，特别是当与合成致死策略相结合时。在本研究中，通过将依喜替康与抗Trop2抗体偶联构建了ADC SA-7-49。通过对DNA损伤反应途径的全面筛选，已确定了喜树碱与胰腺导管腺癌细胞中共济失调毛细血管扩张突变和Rad3相关蛋白（ATR）抑制剂之间的合成致死性。使用零相互作用效价（ZIP）评分对药物相互作用进行量化。采用RNA测序来阐明驱动协同效应的机制。ATR抑制剂通过抑制ATR-Chk1途径诱导细胞凋亡，从而与喜树碱产生协同作用。敲低ATR可增强胰腺导管腺癌细胞对喜树碱和SA-7-49的敏感性。SA-7-49选择性地靶向并根除胰腺导管腺癌细胞和异种移植瘤且无副作用，通过合成致死性增强抗肿瘤活性。我们的研究结果揭示了一种将ADC技术与胰腺导管腺癌的合成致死性相结合的新型治疗策略。
