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| Status |
Public on Jan 22, 2023 |
| Title |
Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC
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| Overall design |
HGSOC KURAMOCHI cells were exposed to 0.1% DMSO (Vehicle control) or 10uM indisulam for 24h before RNA extraction and RNAseq
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| Contributor(s) |
Xu Y, Spear S, Ma Y, Lorentzen MP, Gruet M, McKinney F, Xu Y, Wickremesinghe C, Shepherd MR, McNeish I, Keun HC, Nijhuis A |
| Citation missing |
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| Submission date |
Jan 17, 2023 |
| Last update date |
Jan 22, 2023 |
| Contact name |
Anke Nijhuis |
| E-mail(s) |
a.nijhuis@imperial.ac.uk
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| Organization name |
Imperial College London
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| Street address |
Du Cane road, IRDB building 2nd floor
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| City |
London |
| State/province |
London |
| ZIP/Postal code |
W12 0NN |
| Country |
United Kingdom |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA924703 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE223011_Nijhuis_KURAMOCHI_VC_INDISULAM_humanCounts.tsv.xlsx |
9.7 Mb |
(ftp)(http) |
XLSX |
| GSE223011_Nijhuis_rMATS_Indi_KURAMOCHI_AS_EVENTS.xls.gz |
9.9 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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