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Updated: Oct 13, 2025
Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
Published on: December 9, 2016
Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma
Shivendra Singh1, Waise Quarni1, Maria Goralski2
1Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Abstract:
Aberrant alternative pre-mRNA splicing plays a critical role in MYC-driven cancers and therefore may represent a therapeutic vulnerability. Here, we show that neuroblastoma, a MYC-driven cancer characterized by splicing dysregulation and spliceosomal dependency, requires the splicing factor RBM39 for survival. Indisulam, a “molecular glue” that selectively recruits RBM39 to the CRL4-DCAF15 E3 ubiquitin ligase for proteasomal degradation, is highly efficacious against neuroblastoma, leading to significant responses in multiple high-risk disease models, without overt toxicity. Genetic depletion or indisulam-mediated degradation of RBM39 induces significant genome-wide splicing anomalies and cell death. Mechanistically, the dependency on RBM39 and high-level expression of DCAF15 determine the exquisite sensitivity of neuroblastoma to indisulam. Our data indicate that targeting the dysregulated spliceosome by precisely inhibiting RBM39, a vulnerability in neuroblastoma, is a valid therapeutic strategy.
Insights
Neuroblastoma cancers, driven by MYC, depend on splicing factor RBM39 for survival. The drug indisulam targets RBM39, showing high efficacy and low toxicity in preclinical models, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aberrant alternative pre-mRNA splicing is crucial in MYC-driven cancers, presenting a potential therapeutic vulnerability.
- Neuroblastoma, a MYC-driven cancer, exhibits splicing dysregulation and dependency on the spliceosome for survival.
Purpose of the Study:
- To investigate the role of splicing factor RBM39 in neuroblastoma survival.
- To evaluate the efficacy of indisulam, a molecular glue targeting RBM39, as a therapeutic strategy for neuroblastoma.
Main Methods:
- Investigated neuroblastoma cell dependency on RBM39.
- Utilized indisulam to induce RBM39 degradation via the CRL4-DCAF15 E3 ubiquitin ligase.
- Assessed genome-wide splicing anomalies and cell death upon RBM39 depletion or degradation.
- Correlated neuroblastoma sensitivity to indisulam with RBM39 dependency and DCAF15 expression levels.
Main Results:
- Neuroblastoma requires the splicing factor RBM39 for survival.
- Indisulam demonstrated high efficacy in preclinical neuroblastoma models with no overt toxicity.
- Genetic depletion or indisulam-mediated degradation of RBM39 led to widespread splicing errors and cell death.
- Neuroblastoma sensitivity to indisulam is linked to RBM39 dependency and high DCAF15 expression.
Conclusions:
- Targeting the dysregulated spliceosome by inhibiting RBM39 is a viable therapeutic strategy for neuroblastoma.
- Indisulam's mechanism of action, degrading RBM39, shows significant promise for treating high-risk neuroblastoma.
