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Splicing targeting approaches highlight actionable vulnerabilities in advanced prostate cancer [22Rv1]

ABSTRACT: To investigate if pharmacological inhibition of splicing could uncover novel actionable vulnerabilities in CRPC, we profiled the genome-wide transcriptional changes elicited in 22Rv1 cells by treatment with three drugs that inhibit the splicing through different molecular targets: i. Pladienolide B, that impairs the activity of SF3B1; ii. Indisulam that promote degradation of the splicing factor RBM39; iii. THZ531 inhibits the cyclin dependent kinases (CDK) 12 and 13.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234734 | GEO | 2024/03/06

REPOSITORIES: GEO

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Splicing targeting approaches highlight actionable vulnerabilities in advanced prostate cancer [22Rv1]

Project description:Splicing targeting approaches highlight actionable vulnerabilities in advanced prostate cancer [22Rv1]

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Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (ATAC-Seq)

Project description:Indisulam selectively bridges splicing factor RBM39 to DCAF15 for proteasomal degradation. However, clinical trials indicate that patient stratification based upon the mechanism of action of indisulam may be required to achieve the best response. Here we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation, requires RBM39 for survival, expresses high levels of DCAF15 among different solid tumor lineages, and is the most sensitive cancer lineage to indisulam that achieves therapeutic effect by specifically targeting RBM39 in neuroblastoma. Genetic depletion or proteasomal degradation of RBM39 by indisulam induces drastic splicing event changes in neuroblastoma cells. Through specifically targeting RBM39, indisulam induces exceptional tumor response in multiple high-risk neuroblastoma models. Collectively we demonstrate that high RBM39 dependency and high-level expression of DCAF15 provide indisulam a more efficacious therapeutic window to treating high-risk neuroblastoma.

2021-11-24 | GSE164504 | GEO

Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (RNA-Seq)

2021-11-24 | GSE164505 | GEO

Transcriptomic expression of A549 and SUM159 cells treated with palbociclib and indisulam

Project description:Indisulam is a molecular glue targeting a splicing factor RBM39 for degradation. To assess splicing errors when treating the cells with indisulam, palbociclib and the combination we perform RNA sequencing and analyze splicing errors.

2022-03-03 | GSE197602 | GEO

Transcriptomic analysis of Panc10.05 cells treated with indisulam

Project description:Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15. We generated spontaneoulsy indisulam-resistant Panc10.05 cells and studied their response to indisulam.

2022-04-09 | GSE200281 | GEO

Transcriptomic expression of A549 cells treated with indisulam and sphinx 31

Project description:Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15. We combined indisulam with sphinx 31 (a splicing factor inhibitor) and evaluated their combined activity in inducing splicing errors.

2022-04-09 | GSE200280 | GEO

Indisulam targets RNA splicing and metabolism to serve as a novel therapeutic strategy for high-risk neuroblastoma

Project description:Neuroblastoma is the most common solid tumour in childhood and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be particularlysensitive to indisulam, a molecular glue that selectively targets the RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models indisulam induced rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlighted a particular disruption to cell cycle and metabolism. Metabolic profiling demonstrated metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour without relapse was observed in both xenografts and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss confirmed in vivo. Our data imply that dual targeting of metabolism and RNA splicing with anti-cancer sulfonamides such as indisulam is promising therapeutic approach for high-risk neuroblastoma.

2022-01-13 | PXD022164 | Pride

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Project description: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

2023-01-22 | GSE223011 | GEO

Indisulam targets RNA splicing and metabolism to serve as a novel therapeutic strategy for high risk neuroblastoma

Project description:Neuroblastoma is the most common solid tumour in childhood. Prognosis remains poor for high risk cases despite the use of multimodal treatment, highlighting the urgent need for novel therapeutic strategies. Analysis of cell line drug sensitivity data suggested that among solid tumours neuroblastoma could be the most sensitive to treatment with indisulam (E7070). Indisulam is a clinical aryl sulphonamide and selective promoter of DCAF15-E3-ubiquitin ligase dependent degradation of the RNA splicing factor and transcriptional coactivator RBM39. Here, we demonstrate for the first time that indisulam is highly efficacious in vitro and in vivo in experimental models of neuroblastoma. Indisulam induced rapid depletion of RBM39, accumulation of splicing errors in mRNA and growth inhibition in a DCAF15-dependent manner. Global analysis of protein and RNA alterations in IMR32 cells demonstrated a significant overlap between mis-spliced RNA and decrease in protein levels. Pathway analysis indicated an enrichment for genes involved in cell cycle and one-carbon metabolism, including CDK4 and TYMS. Finally, indisulam induces mitochondrial dysfunction, metabolome perturbations, alterations to redox balance and NAD/NADH ratio in vitro. Metabolic changes were validated in IMR32 xenografts in vivo. Collectively, our data suggest that high-risk neuroblastomas, which are frequently MYCN/MYC-driven, may be particularly susceptible to the dual targeting of metabolism and RNA splicing with anticancer sulfonamides such as indisulam

2021-12-30 | GSE160446 | GEO

Structural complementarity offsets low receptor affinity in E7820-mediated RBM39 degradation by CRL4DCAF15

Project description:The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome and CRL4DCAF15 ubiquitin ligase-dependent mechanism, however the molecular details of this activity remain elusive. Here we present the cryo-EM structure of DDB1-DCAF15-DDA1 bound to RBM39 and E7820 at 4.4 Å resolution, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a novel fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate the low affinity interaction between aryl-sulfonamides and DCAF15. Our data demonstrates how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and RBM23 without the requirement for a high affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

2019-07-10 | PXD014536 | Pride

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