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

Abstract

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.

• Authors: Peng Gu, Liting Xue, Chunyan Zhao, Wenjing Li, Zhen Jiang, Aiguo Liu, Tingting Li, Lu Liu, Markus Decker, Xiaoxuan Cheng, Wenqing Yang, Renhong Tang
• Journal: Frontiers in oncology (Front Oncol) Vol. 12 Pg. 885186 ( 2022) ISSN: 2234-943X [Print] Switzerland
• PMID: 35646698 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Gu, Xue, Zhao, Li, Jiang, Liu, Li, Liu, Decker, Cheng, Yang and Tang.