Imperial College London
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ProfessorHectorKeun

Faculty of Medicine, Department of Surgery & Cancer

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 3161h.keun

 
 
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Location

 

officesInstitute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Nijhuis:2022:10.1038/s41467-022-28907-3,
author = {Nijhuis, A and Sikka, A and Yogev, O and Herendi, L and Balcells, C and Ma, Y and Poon, E and Valbuena, G and Xu, Y and Liu, Y and Martins, da Costa B and Gruet, M and Wickremesinghe, C and Benito, A and Kramer, H and Montoya, A and Carling, D and Want, E and Jamin, Y and Chesler, L and Keun, H},
doi = {10.1038/s41467-022-28907-3},
journal = {Nature Communications},
title = {Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma},
url = {http://dx.doi.org/10.1038/s41467-022-28907-3},
volume = {13},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Nijhuis,A
AU  - Sikka,A
AU  - Yogev,O
AU  - Herendi,L
AU  - Balcells,C
AU  - Ma,Y
AU  - Poon,E
AU  - Valbuena,G
AU  - Xu,Y
AU  - Liu,Y
AU  - Martins,da Costa B
AU  - Gruet,M
AU  - Wickremesinghe,C
AU  - Benito,A
AU  - Kramer,H
AU  - Montoya,A
AU  - Carling,D
AU  - Want,E
AU  - Jamin,Y
AU  - Chesler,L
AU  - Keun,H
DO  - 10.1038/s41467-022-28907-3
PY  - 2022///
SN  - 2041-1723
TI  - Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/s41467-022-28907-3
UR  - http://hdl.handle.net/10044/1/95773
VL  - 13
ER  -
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