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The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer
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The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer
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Journal Article
The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer
2021
Overview
Background
Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC.
Methods
Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC.
Results
We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo.
Conclusions
Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Benzothiazoles - pharmacology
/ Biomedical and Life Sciences
/ Cell Proliferation - drug effects
/ Cystadenocarcinoma, Serous - drug therapy
/ Cystadenocarcinoma, Serous - genetics
/ Cystadenocarcinoma, Serous - pathology
/ DNA
/ DNA Replication - drug effects
/ Drug Resistance, Neoplasm - genetics
/ Female
/ G1 Phase Cell Cycle Checkpoints
/ Genomes
/ Humans
/ M Phase Cell Cycle Checkpoints
/ Mice
/ Naphthyridines - pharmacology
/ Nucleoli
/ Oncology
/ Ovarian Neoplasms - drug therapy
/ Ovarian Neoplasms - genetics
/ Ovarian Neoplasms - pathology
/ Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
/ Ribose
/ RNA Polymerase I - antagonists & inhibitors
/ Topoisomerase I Inhibitors - pharmacology
/ Tumors
