Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma.
View/ Open
Date
2022-03-16Author
Nijhuis, A
Sikka, A
Yogev, O
Herendi, L
Balcells, C
Ma, Y
Poon, E
Eckold, C
Valbuena, GN
Xu, Y
Liu, Y
da Costa, BM
Gruet, M
Wickremesinghe, C
Benito, A
Kramer, H
Montoya, A
Carling, D
Want, EJ
Jamin, Y
Chesler, L
Keun, HC
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Humans
Neuroblastoma
Neoplasm Recurrence, Local
Sulfonamides
Intracellular Signaling Peptides and Proteins
RNA Splicing
Child
N-Myc Proto-Oncogene Protein
Research team
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Language
eng
Date accepted
2022-02-11
License start date
2022-03-16
Citation
Nature communications, 2022, 13 (1), pp. 1380 - ?
Publisher
NATURE PORTFOLIO