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Get Free AccessAbstract 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.
Elaine Sanij, Katherine M. Hannan, Jiachen Xuan, Shunfei Yan, Jessica E. Ahern, Anna Trigos, Natalie Brajanovski, Jinbae Son, Keefe T. Chan, Olga Kondrashova, Elizabeth Lieschke, Matthew J. Wakefield, Daniel Frank, Sarah Ellis, Carleen Cullinane, Jian Kang, Gretchen Poortinga, Purba Nag, Andrew J. Deans, Kum Kum Khanna, Linda Mileshkin, Grant A. McArthur, John Soong, Els M.J.J. Berns, Ross D. Hannan, Clare L. Scott, Karen E. Sheppard, Richard B. Pearson (2020). CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. , 11(1), DOI: https://doi.org/10.1038/s41467-020-16393-4.
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Type
Article
Year
2020
Authors
28
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1038/s41467-020-16393-4
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