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Auranofin attenuates TOPBP1-mediated ATR replication stress response and improves chemotherapeutic response in breast
Shuai Ma1, Yingying Han1, Rui Gu1
1Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Key Laboratory of Blood Science, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University, Tianjin, China.
Abstract:
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.
Insights
Auranofin, an FDA-approved drug, targets TOPBP1 to disrupt replication stress response in cancer cells. This finding reveals its potential for breast tumor intervention, especially when combined with PARP inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Genome instability, often from replication stress, creates vulnerabilities in cancer cells.
- Topoisomerase II binding protein 1 (TOPBP1) is crucial for the ATR-mediated replication stress response and a potential cancer therapeutic target.
Purpose of the Study:
- To identify compounds targeting TOPBP1 for cancer therapy.
- To investigate the mechanism of action and therapeutic potential of auranofin in breast tumors.
Main Methods:
- Drug screening to identify TOPBP1 inhibitors.
- Biochemical assays to assess TOPBP1 interactions and phase separation.
- In vitro and in vivo studies evaluating anti-tumor activity.
Main Results:
- Auranofin binds TOPBP1's BRCT 7-8 domains, inhibiting its interactions with PHF8 and FANCJ.
- Auranofin disrupts TOPBP1 liquid-liquid phase separation, impairing ATR activation and RPA loading.
- Auranofin demonstrates significant anti-breast tumor activity, particularly in combination with a PARP inhibitor.
Conclusions:
- Auranofin effectively targets TOPBP1-mediated replication integrity.
- This FDA-approved drug shows promise for breast tumor intervention, expanding its therapeutic applications.
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