dc.contributor.author | Nijhuis, A | |
dc.contributor.author | Sikka, A | |
dc.contributor.author | Yogev, O | |
dc.contributor.author | Herendi, L | |
dc.contributor.author | Balcells, C | |
dc.contributor.author | Ma, Y | |
dc.contributor.author | Poon, E | |
dc.contributor.author | Eckold, C | |
dc.contributor.author | Valbuena, GN | |
dc.contributor.author | Xu, Y | |
dc.contributor.author | Liu, Y | |
dc.contributor.author | da Costa, BM | |
dc.contributor.author | Gruet, M | |
dc.contributor.author | Wickremesinghe, C | |
dc.contributor.author | Benito, A | |
dc.contributor.author | Kramer, H | |
dc.contributor.author | Montoya, A | |
dc.contributor.author | Carling, D | |
dc.contributor.author | Want, EJ | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Keun, HC | |
dc.date.accessioned | 2022-05-27T09:43:57Z | |
dc.date.available | 2022-05-27T09:43:57Z | |
dc.date.issued | 2022-03-16 | |
dc.identifier.citation | Nature communications, 2022, 13 (1), pp. 1380 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5155 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-022-28907-3 | |
dc.identifier.doi | 10.1038/s41467-022-28907-3 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 1380 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Neuroblastoma | |
dc.subject | Neoplasm Recurrence, Local | |
dc.subject | Sulfonamides | |
dc.subject | Intracellular Signaling Peptides and Proteins | |
dc.subject | RNA Splicing | |
dc.subject | Child | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.title | Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-02-11 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41467-022-28907-3 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2022-03-16 | |
dc.relation.isPartOf | Nature communications | |
pubs.issue | 1 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.publication-status | Published | |
pubs.volume | 13 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
dc.contributor.icrauthor | Poon, Evon | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Chesler, Louis | |