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

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.

• Authors: 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 Nijhawan, Andrew M Davidoff, Jun Yang
• Journal: Science advances (Sci Adv) Vol. 7 Issue 47 Pg. eabj5405 (Nov 19 2021) ISSN: 2375-2548 [Electronic] United States
• PMID: 34788094 (Publication Type: Journal Article)