Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors

Frontiers in Oncology

Xiaoxuan Cheng¹  Aiguo Liu²  Lu Liu²  Renhong Tang²  Wenjing Li²  Zhen Jiang²  Liting Xue²  Markus Decker²  Peng Gu²  Tingting Li²  Wenqing Yang²  Chunyan Zhao² 

[1] High School Sophomore, Hangzhou Foreign Languages School, Hangzhou, China;State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China;

关键词: Keywords: RAD51;    small molecule inhibitor;    DNA damage response;    homologous recombination;    synthetic lethality;   

DOI  :  10.3389/fonc.2022.885186

来源: DOAJ

【 摘 要 】

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 in vivo. 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.

【 授权许可】

Unknown