Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma
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 m...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723013190 |
| _version_ | 1827788677271519232 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuewei Xu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T17:09:54Z |
| format | Article |
| id | doaj.art-f92b72689e9e4fa5ac20d9abaf4deae7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-11T17:09:54Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f92b72689e9e4fa5ac20d9abaf4deae72023-10-20T06:39:31ZengElsevierCell Reports2211-12472023-10-014210113307Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinomaYuewei Xu0Sarah Spear1Yurui Ma2Marc P. Lorentzen3Michael Gruet4Flora McKinney5Yitao Xu6Chiharu Wickremesinghe7Madelen R. Shepherd8Iain McNeish9Hector C. Keun10Anke Nijhuis11Department of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UKDepartment of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK; Corresponding authorDepartment of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723013190CP: Cancer |
| spellingShingle | 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 Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma Cell Reports CP: Cancer |
| title | Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma |
| title_full | Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma |
| title_fullStr | Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma |
| title_full_unstemmed | Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma |
| title_short | Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma |
| title_sort | pharmacological depletion of rna splicing factor rbm39 by indisulam synergizes with parp inhibitors in high grade serous ovarian carcinoma |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723013190 |
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