Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma.
Female
Humans
Animals
Mice
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
BRCA1 Protein
/ genetics
Mutation
RNA Splicing Factors
/ genetics
RNA
BRCA2 Protein
/ genetics
Neoplasm Recurrence, Local
/ drug therapy
Antineoplastic Agents
/ pharmacology
Ovarian Neoplasms
/ drug therapy
RNA Splicing
Phthalazines
/ pharmacology
CP: Cancer
DNA repair
PARP inhibitor
RNA splicing
combination therapy
homolougous recombination
ovarian cancer
ovarian high-grade serous carcinoma
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
31 10 2023
31 10 2023
Historique:
received:
26
04
2023
revised:
04
09
2023
accepted:
04
10
2023
medline:
6
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.
Identifiants
pubmed: 37858464
pii: S2211-1247(23)01319-0
doi: 10.1016/j.celrep.2023.113307
pii:
doi:
Substances chimiques
Poly(ADP-ribose) Polymerase Inhibitors
0
N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
0
BRCA1 protein, human
0
BRCA1 Protein
0
RNA Splicing Factors
0
RNA
63231-63-0
BRCA2 protein, human
0
BRCA2 Protein
0
Antineoplastic Agents
0
Phthalazines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113307Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.