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.
Animals
Benzothiazoles
/ pharmacology
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cystadenocarcinoma, Serous
/ drug therapy
DNA Damage
/ drug effects
DNA Replication
/ drug effects
Drug Resistance, Neoplasm
/ genetics
Drug Synergism
Drug Therapy, Combination
Female
G1 Phase Cell Cycle Checkpoints
Genes, BRCA2
Homologous Recombination
Humans
M Phase Cell Cycle Checkpoints
Mice
Mice, Inbred NOD
Mice, SCID
Naphthyridines
/ pharmacology
Neoplasm Grading
Ovarian Neoplasms
/ drug therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ therapeutic use
RNA Interference
RNA Polymerase I
/ antagonists & inhibitors
Topoisomerase I Inhibitors
/ pharmacology
Topotecan
/ pharmacology
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
10
11
2019
accepted:
22
10
2020
revised:
05
10
2020
pubmed:
12
11
2020
medline:
11
6
2021
entrez:
11
11
2020
Statut:
ppublish
Résumé
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. Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33173151
doi: 10.1038/s41416-020-01158-z
pii: 10.1038/s41416-020-01158-z
pmc: PMC7851142
doi:
Substances chimiques
Benzothiazoles
0
CX 5461
0
Naphthyridines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Topoisomerase I Inhibitors
0
Topotecan
7M7YKX2N15
RNA Polymerase I
EC 2.7.7.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
616-627Références
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