CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer
AuthorSanij, E; Hannan, KM; Xuan, J; Yan, S; Ahern, JE; Trigos, AS; Brajanovski, N; Son, J; Chan, KT; Kondrashova, O; ...
Source TitleNATURE COMMUNICATIONS
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sChan, Keefe; Hannan, Ross; Sanij, Elaine; Pearson, Richard; Wakefield, Matthew; Scott, Clare; Sheppard, Karen; Cullinane, Carleen; Ellis, Sarah; Deans, Andrew; ...
AffiliationMedical Biology (W.E.H.I.)
Medicine and Radiology
Obstetrics and Gynaecology
Biochemistry and Molecular Biology
Sir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsSanij, 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.
Access StatusOpen Access
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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