The DNA damage response (DDR) pathway sets the stage for tumorigenesis and provides both an opportunity for drug efficacy and resistance. Therapeutic approaches to target the DDR pathway include aiming to increase the efficacy of cytotoxic chemotherapies and synergistic drug strategies to enhance DNA damage, and hence cell death. Here, we report the first preclinical evaluation of a novel synergistic approach by using both genetic and small molecule inhibition methods of silencing the DDR related protein, PARG (poly (ADP) ribose glycohydrolase) and the checkpoint kinase inhibitor, Wee1, in pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) cells in vitro and in vivo. Mechanistically, we demonstrate that co-inhibition of PARG and Wee1 synergistically decreased cell survival and increased DNA damage in an S-phase dependent manner. Implications: In pre-clinical models, we demonstrate the efficacy and mechanism of action of targeting both PARG and Wee1 in PDAC and CRC cells.

中文翻译：

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PARG 和 Wee1 的联合靶向以 S 期依赖性方式导致细胞存活率降低和 DNA 损伤

DNA 损伤反应 (DDR) 途径为肿瘤发生奠定了基础，并为药物疗效和耐药性提供了机会。针对 DDR 途径的治疗方法包括旨在提高细胞毒性化学疗法和协同药物策略的功效，以增强 DNA 损伤，从而导致细胞死亡。在这里，我们报告了通过使用遗传和小分子抑制方法使 DDR 相关蛋白 PARG（聚（ADP）核糖糖水解酶）和检查点激酶抑制剂 Wee1 在胰腺导管腺癌中沉默的新型协同方法的首次临床前评估(PDAC) 和结肠直肠癌 (CRC) 细胞在体外和体内。从机制上讲，我们证明 PARG 和 Wee1 的共同抑制以 S 期依赖性方式协同降低细胞存活率并增加 DNA 损伤。