Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

Elaine Sanij, et al.

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Jul 16, 2019

Received Date: 28th June 19

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, 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

Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical
management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA
genes (rDNA), induces replication stress at rDNA 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 repairdeficient 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 involving 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

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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