Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2022-03-16
Date Accepted
2022-02-11
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.
Citation
Nature communications, 2022, 13 (1), pp. 1380 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Research Team
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Pre-Clinical MRI