Gu Peng, Xue Liting, Zhao Chunyan, Li Wenjing, Jiang Zhen, Liu Aiguo, Li Tingting, Liu Lu, Decker Markus, Cheng Xiaoxuan, Yang Wenqing, Tang Renhong
State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China.
High School Sophomore, Hangzhou Foreign Languages School, Hangzhou, China.
Front Oncol. 2022 May 13;12:885186. doi: 10.3389/fonc.2022.885186. eCollection 2022.
Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth . By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment.
靶向DNA损伤反应（DDR）途径已被提议作为一种放大肿瘤特异性复制性损伤的方法。RAD51在DDR过程中起核心作用，因此是一个有前景的抗肿瘤靶点。我们在此报告发现了一系列能够阻止RAD51焦点形成的新一代RAD51抑制剂。先导化合物显著损害人类癌细胞生长，诱导细胞周期停滞于S期，并导致γH2AX升高。此外，癌细胞对化疗和其他DDR抑制剂变得敏感。这些化合物无论是作为单一药物给药还是与顺铂联合给药，均能显著抑制肿瘤生长。通过上调ATR-CHK1信号传导，RAD51抑制剂增加了各种肿瘤细胞表面的PD-L1水平，提示RAD51抑制剂与PD-1/PD-L1阻断剂联合使用的可能性。总体而言，我们的研究结果为探索将RAD51抑制剂作为单一疗法或与化疗、免疫疗法或DDR靶向疗法联合用于癌症治疗提供了临床前理论依据。
