Journal
BRITISH JOURNAL OF CANCER
Volume 124, Issue 3, Pages 616-627Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-020-01158-z
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Funding
- China Scholarship Council University of Melbourne
- National Health and Medical Research Council (NHMRC)
- NHMRC Senior Research Fellowship
- Australian Cancer Research Foundation (ACRF)
- Australian Phenomics Network (APN) from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) programme
- Peter MacCallum Cancer Centre Foundation
- University of Melbourne Research Collaborative Infrastructure Programme
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In this study, TOP1 inhibition was found to enhance the therapeutic effect of CX-5461 in targeting HR-proficient HGSC by inducing a nucleolar DNA damage response and global replication stress, ultimately reducing clonogenic survival and tumor growth.
Background Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC. Methods Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. Results We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo. Conclusions Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.
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