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Series GSE223011 Query DataSets for GSE223011
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
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
Overall design HGSOC KURAMOCHI cells were exposed to 0.1% DMSO (Vehicle control) or 10uM indisulam for 24h before RNA extraction and RNAseq
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
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Submission date Jan 17, 2023
Last update date Jan 22, 2023
Contact name Anke Nijhuis
Organization name Imperial College London
Street address Du Cane road, IRDB building 2nd floor
City London
State/province London
ZIP/Postal code W12 0NN
Country United Kingdom
Platforms (1)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (6)
GSM6938250 KURAMOCHI, Vehicle, 24h, rep 1
GSM6938251 KURAMOCHI, 10uM indisulam, 24h, rep 1
GSM6938252 KURAMOCHI, Vehicle, 24h, rep 2
BioProject PRJNA924703

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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
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Processed data are available on Series record

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