Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2023-10-31
Date Acceptance
2023-10-04
Citation
Cell Reports, 2023, 42 (10)
ISSN
2211-1247
Publisher
Elsevier
Journal / Book Title
Cell Reports
Volume
42
Issue
10
Copyright Statement
© 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
License URL
(http://creativecommons.org/licenses/by/4.0/
Publication Status
Published
Article Number
ARTN 113307
Date Publish Online
2023-10-19