Auranofin attenuates TOPBP1-mediated ATR replication stress response and improves chemotherapeutic response in breast tumor models
Genome instability is most commonly caused by replication stress, which also renders cancer cells extremely vulnerable once their response to replication stress is impeded. Topoisomerase II binding protein 1 (TOPBP1), an allosteric activator of ataxia telangiectasia and Rad3-related kinase (ATR), coordinates ATR in replication stress response and has emerged as a potential therapeutic target for tumors. Here, we identify auranofin, the FDA-approved drug for rheumatoid arthritis, as a lead compound capable of binding to the BRCT 7-8 domains and blocking TOPBP1 interaction with PHF8 and FANCJ. The liquid-liquid phase separation of TOPBP1 is also disrupted by auranofin. Through targeting these TOPBP1-nucleated molecular machineries, auranofin leads to an accumulation of replication defects by impairing ATR activation and attenuating replication protein A loading on perturbed replication forks, and it shows significant anti-breast tumor activity in combination with a PARP inhibitor. This study provides mechanistic insights into how auranofin challenges replication integrity and expands the application of this FDA-approved drug in breast tumor intervention.
Authors
- Zhi Yao (ORCID: https://orcid.org/0000-0002-9490-3870)
- Lei Shi (ORCID: https://orcid.org/0000-0003-1679-3618)
- Jie Yang (ORCID: https://orcid.org/0000-0002-8348-7250)
- Zhenzhen Yang (ORCID: https://orcid.org/0000-0002-0233-4747)
- Yuan Yue (ORCID: https://orcid.org/0000-0002-4818-9063)
- Qiushi Guo (ORCID: https://orcid.org/0000-0003-4514-9469)
- Xiaoyun Mao (ORCID: https://orcid.org/0000-0003-4755-0301)
- Yan Qin (ORCID: https://orcid.org/0000-0003-3640-0105)
- Rui Gu
- Kai Zhang (ORCID: https://orcid.org/0000-0003-2800-0531)
- Ling Liu (ORCID: https://orcid.org/0000-0002-4347-4252)
- Lin Liu (ORCID: https://orcid.org/0000-0001-7314-4425)
- Cheng Cao (ORCID: https://orcid.org/0000-0003-4406-747X)
- Na Yang (ORCID: https://orcid.org/0000-0002-6956-6630)
- Shuai Ma
- Yingying Han (ORCID: https://orcid.org/0000-0002-9520-6778)
- Qi Chen (ORCID: https://orcid.org/0000-0002-7095-776X)
- Ying Yang (ORCID: https://orcid.org/0000-0001-5277-1155)
- Jihui Hao (ORCID: https://orcid.org/0000-0002-5598-6706)
- Fei Liu (ORCID: https://orcid.org/0009-0005-0576-440X)
Institutions
- University of Science and Technology of China (CN)
- Capital Medical University (CN)
- Nankai University (CN)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- First Affiliated Hospital of Liaoning Medical University (CN)
- China Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1172/jci180106
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00