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

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Title: Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
Authors: Nijhuis, A
Sikka, A
Yogev, O
Herendi, L
Balcells, C
Ma, Y
Poon, E
Valbuena, G
Xu, Y
Liu, Y
Martins da Costa, B
Gruet, M
Wickremesinghe, C
Benito, A
Kramer, H
Montoya, A
Carling, D
Want, E
Jamin, Y
Chesler, L
Keun, H
Item Type: Journal Article
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.
Issue Date: 16-Mar-2022
Date of Acceptance: 11-Feb-2022
URI: http://hdl.handle.net/10044/1/95773
DOI: 10.1038/s41467-022-28907-3
ISSN: 2041-1723
Publisher: Nature Research
Journal / Book Title: Nature Communications
Volume: 13
Copyright Statement: © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Commission of the European Communities
Astra Zeneca Pharmaceuticals
Funder's Grant Number: 737978
Publication Status: Published
Article Number: ARTN 1380
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Institute of Clinical Sciences
Faculty of Medicine

This item is licensed under a Creative Commons License Creative Commons