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

Elaine Sanij (), Katherine M. Hannan (), Jiachen Xuan, Shunfei Yan, Jessica E. Ahern, Anna S. 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 and Richard B. Pearson ()
Additional contact information
Elaine Sanij: Peter MacCallum Cancer Centre
Katherine M. Hannan: Australian National University
Jiachen Xuan: Peter MacCallum Cancer Centre
Shunfei Yan: Peter MacCallum Cancer Centre
Jessica E. Ahern: Peter MacCallum Cancer Centre
Anna S. Trigos: Peter MacCallum Cancer Centre
Natalie Brajanovski: Peter MacCallum Cancer Centre
Jinbae Son: Peter MacCallum Cancer Centre
Keefe T. Chan: Peter MacCallum Cancer Centre
Olga Kondrashova: The Walter and Eliza Hall Institute of Medical Research
Elizabeth Lieschke: The Walter and Eliza Hall Institute of Medical Research
Matthew J. Wakefield: The Walter and Eliza Hall Institute of Medical Research
Daniel Frank: The Walter and Eliza Hall Institute of Medical Research
Sarah Ellis: Peter MacCallum Cancer Centre
Carleen Cullinane: Peter MacCallum Cancer Centre
Jian Kang: Peter MacCallum Cancer Centre
Gretchen Poortinga: Peter MacCallum Cancer Centre
Purba Nag: QIMR Berghofer Medical Research Institute
Andrew J. Deans: University of Melbourne
Kum Kum Khanna: QIMR Berghofer Medical Research Institute
Linda Mileshkin: Peter MacCallum Cancer Centre
Grant A. McArthur: Peter MacCallum Cancer Centre
John Soong: Virginia Commonwealth University School of Medicine
Els M. J. J. Berns: Erasmus MC Cancer Institute
Ross D. Hannan: Peter MacCallum Cancer Centre
Clare L. Scott: Peter MacCallum Cancer Centre
Karen E. Sheppard: Peter MacCallum Cancer Centre
Richard B. Pearson: Peter MacCallum Cancer Centre

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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 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.

Date: 2020
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DOI: 10.1038/s41467-020-16393-4

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