CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer.
Animals
Benzothiazoles
/ pharmacology
Cell Line, Tumor
Cystadenocarcinoma, Serous
/ drug therapy
DNA Damage
DNA Replication
/ drug effects
Drug Resistance, Neoplasm
Enzyme Inhibitors
/ pharmacology
Female
Heterografts
Homologous Recombination
Humans
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Models, Biological
Naphthyridines
/ pharmacology
Ovarian Neoplasms
/ drug therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
RNA Polymerase I
/ antagonists & inhibitors
Transcriptome
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 05 2020
26 05 2020
Historique:
received:
28
06
2019
accepted:
30
04
2020
entrez:
28
5
2020
pubmed:
28
5
2020
medline:
25
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32457376
doi: 10.1038/s41467-020-16393-4
pii: 10.1038/s41467-020-16393-4
pmc: PMC7251123
doi:
Substances chimiques
Benzothiazoles
0
CX 5461
0
Enzyme Inhibitors
0
Naphthyridines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
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
2641Références
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