University Library
  • Login
A gateway to Melbourne's research publications
Minerva Access is the University's Institutional Repository. It aims to collect, preserve, and showcase the intellectual output of staff and students of the University of Melbourne for a global audience.
View Item 
  • Minerva Access
  • Medicine, Dentistry & Health Sciences
  • Sir Peter MacCallum Department of Oncology
  • Sir Peter MacCallum Department of Oncology - Research Publications
  • View Item
  • Minerva Access
  • Medicine, Dentistry & Health Sciences
  • Sir Peter MacCallum Department of Oncology
  • Sir Peter MacCallum Department of Oncology - Research Publications
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

    The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer

    Thumbnail
    Download
    Published version (4.362Mb)

    Citations
    Altmetric
    Author
    Yan, S; Xuan, J; Brajanovski, N; Tancock, MRC; Madhamshettiwar, PB; Simpson, KJ; Ellis, S; Kang, J; Cullinane, C; Sheppard, KE; ...
    Date
    2020-11-11
    Source Title
    British Journal of Cancer
    Publisher
    Springer Nature
    University of Melbourne Author/s
    Chan, Keefe; Sanij, Elaine; Hannan, Katherine
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Biochemistry and Molecular Biology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Yan, S., Xuan, J., Brajanovski, N., Tancock, M. R. C., Madhamshettiwar, P. B., Simpson, K. J., Ellis, S., Kang, J., Cullinane, C., Sheppard, K. E., Hannan, K. M., Hannan, R. D., Sanij, E., Pearson, R. B. & Chan, K. T. (2020). The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer. British Journal of Cancer (BJC), 124 (3), https://doi.org/10.1038/s41416-020-01158-z.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251363
    DOI
    10.1038/s41416-020-01158-z
    Open Access URL
    https://www.nature.com/articles/s41416-020-01158-z
    Abstract
    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.

    Export Reference in RIS Format     

    Endnote

    • Click on "Export Reference in RIS Format" and choose "open with... Endnote".

    Refworks

    • Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References


    Collections
    • Minerva Elements Records [52443]
    • Biochemistry and Molecular Biology - Research Publications [1067]
    • Sir Peter MacCallum Department of Oncology - Research Publications [1029]
    Minerva AccessDepositing Your Work (for University of Melbourne Staff and Students)NewsFAQs

    BrowseCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects
    My AccountLoginRegister
    StatisticsMost Popular ItemsStatistics by CountryMost Popular Authors