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dc.contributor.authorSanij, Elaine
dc.contributor.authorHannan, Katherine M
dc.contributor.authorXuan, Jiachen
dc.contributor.authorYan, Shunfei
dc.contributor.authorAhern, Jessica E
dc.contributor.authorTrigos, Anna S
dc.contributor.authorBrajanovski, Natalie
dc.contributor.authorSon, Jinbae
dc.contributor.authorChan, Keefe T
dc.contributor.authorKondrashova, Olga
dc.contributor.authorLieschke, Elizabeth
dc.contributor.authorWakefield, Matthew J
dc.contributor.authorFrank, Daniel
dc.contributor.authorKhanna, Kum Kum
dc.contributor.authoret al.
dc.date.accessioned2020-09-15T05:50:39Z
dc.date.available2020-09-15T05:50:39Z
dc.date.issued2020
dc.identifier.issn2041-1723en_US
dc.identifier.doi10.1038/s41467-020-16393-4en_US
dc.identifier.urihttp://hdl.handle.net/10072/397525
dc.description.abstractAcquired 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.en_US
dc.description.peerreviewedYesen_US
dc.languageEnglishen_US
dc.language.isoeng
dc.publisherNATURE PUBLISHING GROUPen_US
dc.relation.ispartofissue1en_US
dc.relation.ispartofjournalNATURE COMMUNICATIONSen_US
dc.relation.ispartofvolume11en_US
dc.subject.fieldofresearchMedical and Health Sciencesen_US
dc.subject.fieldofresearchBiological Sciencesen_US
dc.subject.fieldofresearchcode11en_US
dc.subject.fieldofresearchcode06en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsMultidisciplinary Sciencesen_US
dc.subject.keywordsScience & Technology - Other Topicsen_US
dc.subject.keywordsRNA-POLYMERASE Ien_US
dc.subject.keywordsHOMOLOGOUS-RECOMBINATIONen_US
dc.titleCX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian canceren_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationSanij, E; Hannan, KM; Xuan, J; Yan, S; Ahern, JE; Trigos, AS; Brajanovski, N; Son, J; Chan, KT; Kondrashova, O; Lieschke, E; Wakefield, MJ; Frank, D; Khanna, KK; et al., RB, CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer, NATURE COMMUNICATIONS, 2020, 11 (1)en_US
dcterms.dateAccepted2020-04-30
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2020-09-15T05:48:01Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© 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/.en_US
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gro.griffith.authorKhanna, Kum K.


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