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CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer

Author

Listed:
  • Elaine Sanij

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • Katherine M. Hannan

    (Australian National University
    University of Melbourne)

  • Jiachen Xuan

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Shunfei Yan

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Jessica E. Ahern

    (Peter MacCallum Cancer Centre)

  • Anna S. Trigos

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Natalie Brajanovski

    (Peter MacCallum Cancer Centre)

  • Jinbae Son

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Keefe T. Chan

    (Peter MacCallum Cancer Centre)

  • Olga Kondrashova

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Elizabeth Lieschke

    (The Walter and Eliza Hall Institute of Medical Research)

  • Matthew J. Wakefield

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Daniel Frank

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Sarah Ellis

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Carleen Cullinane

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Jian Kang

    (Peter MacCallum Cancer Centre)

  • Gretchen Poortinga

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • Purba Nag

    (QIMR Berghofer Medical Research Institute
    Griffith University)

  • Andrew J. Deans

    (University of Melbourne
    St Vincent’s Institute)

  • Kum Kum Khanna

    (QIMR Berghofer Medical Research Institute)

  • Linda Mileshkin

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Grant A. McArthur

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne
    University of Melbourne)

  • John Soong

    (Virginia Commonwealth University School of Medicine)

  • Els M. J. J. Berns

    (Erasmus MC Cancer Institute)

  • Ross D. Hannan

    (Peter MacCallum Cancer Centre
    University of Melbourne
    Australian National University
    University of Melbourne)

  • Clare L. Scott

    (Peter MacCallum Cancer Centre
    The Walter and Eliza Hall Institute of Medical Research
    Monash University)

  • Karen E. Sheppard

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • Richard B. Pearson

    (Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne
    Monash University)

Abstract

Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

Suggested Citation

  • Elaine Sanij & Katherine M. Hannan & Jiachen Xuan & Shunfei Yan & Jessica E. Ahern & Anna S. Trigos & Natalie Brajanovski & Jinbae Son & Keefe T. Chan & Olga Kondrashova & Elizabeth Lieschke & Matthew, 2020. "CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16393-4
    DOI: 10.1038/s41467-020-16393-4
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    Cited by:

    1. Min Pan & William C. Wright & Richard H. Chapple & Asif Zubair & Manbir Sandhu & Jake E. Batchelder & Brandt C. Huddle & Jonathan Low & Kaley B. Blankenship & Yingzhe Wang & Brittney Gordon & Payton A, 2021. "The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.

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