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

Anke Nijhuis, Arti Sikka, Orli Yogev, Lili Herendi, Cristina Balcells, Yurui Ma, Evon Poon, Clare Eckold, Gabriel N. Valbuena, Yuewei Xu, Yusong Liu, Barbara Martins Costa, Michael Gruet, Chiharu Wickremesinghe, Adrian Benito, Holger Kramer, Alex Montoya, David Carling, Elizabeth J. Want, Yann Jamin, Louis Chesler and Hector C. Keun ()
Additional contact information
Anke Nijhuis: Imperial College London
Arti Sikka: Imperial College London
Orli Yogev: The Institute of Cancer Research
Lili Herendi: Imperial College London
Cristina Balcells: Imperial College London
Yurui Ma: Imperial College London
Evon Poon: The Institute of Cancer Research
Clare Eckold: Imperial College London
Gabriel N. Valbuena: Imperial College London
Yuewei Xu: Imperial College London
Yusong Liu: Imperial College London
Barbara Martins Costa: The Institute of Cancer Research
Michael Gruet: Imperial College London
Chiharu Wickremesinghe: Imperial College London
Adrian Benito: Imperial College London
Holger Kramer: Medical Research Council London Institute of Medical Science
Alex Montoya: Medical Research Council London Institute of Medical Science
David Carling: Medical Research Council London Institute of Medical Science
Elizabeth J. Want: Digestion and Reproduction, Imperial College London
Yann Jamin: The Institute of Cancer Research, London and Royal Marsden NHS Trust
Louis Chesler: The Institute of Cancer Research
Hector C. Keun: Imperial College London

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28907-3

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