Journal article

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 Show all

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2020

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 v..

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Grants

Awarded by NHMRC Program Grant


Funding Acknowledgements

We thank Jason Ellul for assistance in analysing OVCA cell lines gene expression data. We thank the Peter MacCallum Cancer Centre FACS Facility, Victorian Centre for Functional Genomics, Centre for Advanced Histology and Microscopy, Laboratory Services and Media Kitchen. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia project grants and a NHMRC Program Grant (#1053792 and #1162052). Researchers were funded by NHMRC Fellowships (K.K., G.A.M., R.D.H., R.B.P.). This research was also supported by the Australian Cancer Research Foundation for the Peter Mac Centre for Advanced Histology and Microscopy facility.