Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Exploiting the polypharmacology of alectinib for synergistic RNA splicing disruption with RBM39 degraders

ABSTRACT: Precise control of pre-mRNA splicing is critical for transcriptome integrity, and its disruption is increasingly recognised as a vulnerability in cancer. Here, we identify a functional interplay between two key splicing regulators, RBM39 and serine/arginine protein kinase 1 (SRPK1), and show that dual targeting of these factors severely compromises splicing fidelity in high-risk neuroblastoma. We use the molecular glue indisulam to degrade RBM39 and repurpose the clinical ALK inhibitor alectinib which potently inhibits SRPK1. Co-treatment with indisulam and alectinib inhibited cell proliferation, induced apoptosis, and caused G2–M arrest in multiple cancer cell lines, including MYCN-amplified neuroblastoma. RNA sequencing revealed enhanced splicing defects preferentially in DNA repair and genome maintenance related genes following combination treatment, leading to R-loop accumulation and increased DNA damage. In the Th-MYCN/ALKF1174L neuroblastoma mouse model, combination therapy induced complete tumour regression and significantly improved survival rates compared with monotherapies. These findings demonstrate that combining indisulam and alectinib is a promising approach to treat aggressive malignancies such as high-risk neuroblastoma, exploiting the previously untapped polypharmacology of alectinib as a clinical RNA splicing inhibitor and supporting the therapeutic value of co-targeting interdependent splicing factors for synergistic benefit.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299818 | GEO | 2025/11/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Exploiting the polypharmacology of alectinib for synergistic RNA splicing disruption with RBM39 degraders

Project description:Exploiting the polypharmacology of alectinib for synergistic RNA splicing disruption with RBM39 degraders

| PRJNA1276571 | ENA

Exceptional response of high-risk neuroblastoma to RBM39 degrader Indisulam (RNA-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 | GSE164505 | GEO

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

2021-11-24 | GSE164504 | 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

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

The aryl sulfonamide indisulam inhibits acute megakaryoblastic leukemia (AMKL) by altering the alternative splicing of the transcription factor ZMYND8

Project description:Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia with clinical heterogeneity. The poor prognosis of AMKL means that new therapies need to be developed to treat this disease. Studies have shown that the dysregulation of alternative splicing is associated with the occurrence and development of AMKL and the increase of chemotherapy resistance. indisulam, as a synthetic aryl sulfonamide, can effectively treat solid tumors by targeting the splicing factor RBM39. However, the effects of indisulam on AMKL and the underlying molecular mechanisms remain to be thoroughly investigated. We first screened AMKL for indisulam susceptibility in a public drug-susceptibility database. The results showed that AMKL was more sensitive to insulin than other tumor types. We then treated human AMKL cell lines (CMK, MEG01 and M07e) with indisulam to evaluate its efficacy and investigate its molecular targets. The results suggest that indisulam induces RBM39 degradation and inhibits tumor growth in a dose-dependent manner. RNA-seq and proteomic analyses revealed that indisulam selectively degraded RBM39 and resulted in mis-splicing of the transcription factor ZMYND8, which maintains AML survival and proliferation. We knocked down ZMYND8 and confirmed the critical role of ZMYND8 in maintaining AMKL survival and proliferation. In addition, we verified that the anti-tumor effect of indisulam on AMKL was DCAF15 dependent. By targeting DCAF15 using CRISPR/Cas9 system, we confirmed the DCAF15-dependent effect of indisulam in both in vivo and in vitro models. Taken together, our study suggests that indisulam has promising therapeutic potential for AMKL by specifically targeting the splicing factor RBM39 and is dependent on the expression of DCAF15. In addition, our study identified ZMYND8 as a novel downstream regulator of RBM39 and the RBM39-ZMYND8 axis is important for AMKL survival and proliferation.

2025-04-23 | GSE266925 | 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

Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [RNA-seq]

Project description:The lineage plasticity of neuroblastoma cells is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which presumably contributes to therapy resistance. However, how the neuroblastoma cells switch their cell states during therapy remains largely unknown and how to eradicate neuroblastoma cells regardless of their cell state alterations is a clinical challenge. By using four distinct human and murine neuroblastoma models treated with indisulam, a molecular glue drug serving as a selective RBM39 degrader, we show that cancer cells not only can undergo bidirectional switch of ADRN and MES cell states, but also can acquire additional cell states of melanoma and Schwann cell progenitors, reminiscent of the cellular pliancy of neural crest cells. The lineage alterations of neuroblastoma cells are coupled with epigenetic changes and dependency switch of lineage-specific transcription factors. Nevertheless, indisulam treatment induces an inflamed tumor microenvironment leading to an immune cell infiltration. The combination of indisulam with anti-GD2 monoclonal immunotherapy results in a durable complete response in transgenic neuroblastoma models driven by MYCN and ALK mutant oncogenes, providing a therapeutic rationale to eradicate tumor cells even when they acquire alternative cell lineage(s) in response to treatment.

2025-06-05 | GSE251918 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data