Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma

Anke Nijhuis, Arti Sikka, Orli Yogev, Lili Herendi, Cristina Balcells, Yurui Ma, Evon Poon, Clare Eckold, Gabriel N. Valbuena, Yuewei Xu, Yusong Liu, Barbara Martins da Costa, Michael Gruet, Chiharu Wickremesinghe, Adrian Benito, Holger Kramer, Alex Montoya, David Carling, Elizabeth J. Want, Yann JaminLouis Chesler, Hector C. Keun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Neuroblastoma is the most common paediatric solid tumour 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 sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induces rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15-dependent manner. Integrative analysis of RNAseq and proteomics data highlight a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrates metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour regression without relapse was observed in both xenograft and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss, RNA splicing and metabolic changes confirmed in vivo. Our data show that dual-targeting of metabolism and RNA splicing with anticancer indisulam is a promising therapeutic approach for high-risk neuroblastoma.

Original languageEnglish
Article number1380
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes

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