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Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma models

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Murray,  Peter J.
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

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sciadv.abj5405.pdf
(Publisher version), 13MB

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sciadv.abj5405_tables_s1_to_s12.zip
(Supplementary material), 19MB

Citation

Singh, S., Quarni, W., Goralski, M., Wan, S., Jin, H., Van de Velde, L.-A., et al. (2021). Targeting the spliceosome through RBM39 degradation results in exceptional responses in high-risk neuroblastoma models. Science Advances, 7(47): eabj5405. doi:10.1126/sciadv.abj5405.


Cite as: https://hdl.handle.net/21.11116/0000-0009-95A4-5
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.