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

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    Khanna428152-Published.pdf (8.592Mb)
    Author(s)
    Sanij, Elaine
    Hannan, Katherine M
    Xuan, Jiachen
    Yan, Shunfei
    Ahern, Jessica E
    Trigos, Anna S
    Brajanovski, Natalie
    Son, Jinbae
    Chan, Keefe T
    Kondrashova, Olga
    Lieschke, Elizabeth
    Wakefield, Matthew J
    Frank, Daniel
    Khanna, Kum Kum
    et al.
    Griffith University Author(s)
    Khanna, Kum K.
    Year published
    2020
    Metadata
    Show full item record
    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 ...
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    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.
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    Journal Title
    NATURE COMMUNICATIONS
    Volume
    11
    Issue
    1
    DOI
    https://doi.org/10.1038/s41467-020-16393-4
    Copyright Statement
    © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
    Subject
    Medical and Health Sciences
    Biological Sciences
    Science & Technology
    Multidisciplinary Sciences
    Science & Technology - Other Topics
    RNA-POLYMERASE I
    HOMOLOGOUS-RECOMBINATION
    Publication URI
    http://hdl.handle.net/10072/397525
    Collection
    • Journal articles

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