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

Shivendra Singh, Waise Quarni, Maria Goralski, Shibiao Wan, Hongjian Jin, Lee Ann van de Velde, Jie Fang, Qiong Wu, Ahmed Abu-Zaid, Tingting Wang, Ravi Singh, David Craft, Yiping Fan, Thomas Confer, Melissa Johnson, Walter J. Akers, Ruoning Wang, Peter J. Murray, Paul G. Thomas, Deepak NijhawanAndrew M. Davidoff, Jun Yang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article numbereabj5405
JournalScience Advances
Volume7
Issue number47
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • General

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