Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma
Yuewei Xu,
Sarah Spear,
Yurui Ma,
Marc P. Lorentzen,
Michael Gruet,
Flora McKinney,
Yitao Xu,
Chiharu Wickremesinghe,
Madelen R. Shepherd,
Iain McNeish,
Hector C. Keun,
Anke Nijhuis
Affiliations
Yuewei Xu
Department of Surgery & Cancer, Imperial College London, London, UK
Sarah Spear
Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Yurui Ma
Department of Surgery & Cancer, Imperial College London, London, UK
Marc P. Lorentzen
Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Michael Gruet
Department of Surgery & Cancer, Imperial College London, London, UK
Flora McKinney
Department of Surgery & Cancer, Imperial College London, London, UK
Yitao Xu
Department of Surgery & Cancer, Imperial College London, London, UK
Chiharu Wickremesinghe
Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Madelen R. Shepherd
Department of Surgery & Cancer, Imperial College London, London, UK
Iain McNeish
Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Hector C. Keun
Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK; Corresponding author
Anke Nijhuis
Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK; Corresponding author
Summary: 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.
