4.7 Article

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer

Journal

CELL DEATH & DISEASE
Volume 12, Issue 4, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41419-021-03665-0

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Funding

  1. Barts and The London Charity Strategic Research Grant [467/2244]
  2. Barts Cancer Institute Incentivisation Award
  3. Cancer Research UK Advanced Clinician Scientist Fellowship [C41405/A19694]
  4. Cancer Research UK Clinician Scientist Fellowship [C41405/A13034]

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Chloroxine restores sensitivity to platinum-based chemotherapy in high-grade serous cancer by overriding DNA damage tolerance, suggesting a promising combination therapy for patient benefit.
High-grade serous cancer (HGSC) accounts for similar to 67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine's predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in gamma H2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.

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