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dc.contributor.authorSanij, E
dc.contributor.authorHannan, KM
dc.contributor.authorXuan, J
dc.contributor.authorYan, S
dc.contributor.authorAhern, JE
dc.contributor.authorTrigos, AS
dc.contributor.authorBrajanovski, N
dc.contributor.authorSon, J
dc.contributor.authorChan, KT
dc.contributor.authorKondrashova, O
dc.contributor.authorLieschke, E
dc.contributor.authorWakefield, MJ
dc.contributor.authorFrank, D
dc.contributor.authorEllis, S
dc.contributor.authorCullinane, C
dc.contributor.authorKang, J
dc.contributor.authorPoortinga, G
dc.contributor.authorNag, P
dc.contributor.authorDeans, AJ
dc.contributor.authorKhanna, KK
dc.contributor.authorMileshkin, L
dc.contributor.authorMcArthur, GA
dc.contributor.authorSoong, J
dc.contributor.authorBerns, EMJJ
dc.contributor.authorHannan, RD
dc.contributor.authorScott, CL
dc.contributor.authorSheppard, KE
dc.contributor.authorPearson, RB
dc.date.accessioned2020-06-11T23:15:48Z
dc.date.available2020-06-11T23:15:48Z
dc.date.issued2020-05-26
dc.identifierpii: 10.1038/s41467-020-16393-4
dc.identifier.citationSanij, E., Hannan, K. M., Xuan, J., Yan, S., Ahern, J. E., Trigos, A. S., Brajanovski, N., Son, J., Chan, K. T., Kondrashova, O., Lieschke, E., Wakefield, M. J., Frank, D., Ellis, S., Cullinane, C., Kang, J., Poortinga, G., Nag, P., Deans, A. J. ,... Pearson, R. B. (2020). CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. NATURE COMMUNICATIONS, 11 (1), https://doi.org/10.1038/s41467-020-16393-4.
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/11343/240470
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.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.titleCX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer
dc.typeJournal Article
dc.identifier.doi10.1038/s41467-020-16393-4
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentMedical Education
melbourne.affiliation.departmentMedicine and Radiology
melbourne.affiliation.departmentObstetrics and Gynaecology
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.source.titleNATURE COMMUNICATIONS
melbourne.source.volume11
melbourne.source.issue1
melbourne.source.pages2641 - ?
melbourne.identifier.nhmrc1053792
melbourne.identifier.nhmrc1162052
dc.rights.licenseCC BY
melbourne.elementsid1450616
melbourne.contributor.authorChan, Keefe
melbourne.contributor.authorHannan, Ross
melbourne.contributor.authorSanij, Elaine
melbourne.contributor.authorPearson, Richard
melbourne.contributor.authorWakefield, Matthew
melbourne.contributor.authorScott, Clare
melbourne.contributor.authorSheppard, Karen
melbourne.contributor.authorCullinane, Carleen
melbourne.contributor.authorEllis, Sarah
melbourne.contributor.authorDeans, Andrew
melbourne.contributor.authorHannan, Katherine
melbourne.contributor.authorPoortinga, Gretchen
melbourne.contributor.authorKondrashova, Olga
melbourne.contributor.authorMcArthur, Grant
melbourne.contributor.authorMileshkin, Linda
melbourne.contributor.authorTrigos, Anna
melbourne.contributor.authorKang, Jian
melbourne.contributor.authorFrank, Daniel
melbourne.contributor.authorLieschke, Elizabeth
melbourne.contributor.authorXuan, Jiachen
melbourne.contributor.authorYan, Shunfei
melbourne.contributor.authorSon, Jinbae
dc.identifier.eissn2041-1723
melbourne.identifier.fundernameidNHMRC, 1053792
melbourne.identifier.fundernameidNHMRC, 1162052
melbourne.accessrightsOpen Access


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