Pharmacological disruption of RNA splicing inhibits ovarian cancer growth and synergises with PARP inhibitors
File(s)
Author(s)
Xu, Yuewei
Type
Thesis
Abstract
High-grade serous ovarian cancer is the most common and lethal subtype of ovarian cancer with limited therapeutic options. Although PARP inhibitor maintenance therapy has shown considerable clinical benefits in ovarian cancer patients, the emergence of acquired drug resistance is a major challenge. Splicing factors coordinate splicing of pre-mRNAs, and they have been implicated in many biological processes including DNA repair. The splicing factor RBM39, in particular, is a promising cancer target, which can be rapidly depleted using the newly identified molecular glue indisulam. In this thesis, I characterised the role of RBM39 in HGSOC cells and found that RBM39 mediates the adaptive response to PARP inhibitors. Indisulam promotes the recruitment of RBM39 to the DCAF15-associated E3 ubiquitin ligase complex, leading to polyubiquitination and proteasomal degradation of RBM39. In HGSOC cells, loss of RBM39 caused widespread splicing defects and significantly reduced protein expression of many DNA repair genes, leading to growth inhibition and increased sensitivity to PARP inhibition in vitro and in vivo. Indisulam suppressed olaparib-induced activation of the ATM-Chk2 and Chk1 signalling pathways, resulting in higher levels of DNA damage, replication abnormalities, and apoptosis. Using a variety of HGSOC models, I showed that indisulam synergises with multiple PARP inhibitors in a DCAF15-dependent manner regardless of BRCA status. Overall, data from this thesis suggest that depleting RBM39 with indisulam is a promising therapeutic strategy to improve PARP inhibitor response in patients with HGSOC, which may benefit a wide range of patients irrespective of BRCA status.
Version
Open Access
Date Issued
2022-10
Date Awarded
2023-02
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Keun, Hector
Nijhuis, Anke
Sponsor
Imperial College London
China Scholarship Council
Grant Number
201808060050
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)