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

Author

Listed:
  • 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
    Digestion and Reproduction, Imperial College London)

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.

Suggested Citation

  • 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 &, 2022. "Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28907-3
    DOI: 10.1038/s41467-022-28907-3
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    Cited by:

    1. Sébastien Campagne & Daniel Jutzi & Florian Malard & Maja Matoga & Ksenija Romane & Miki Feldmuller & Martino Colombo & Marc-David Ruepp & Frédéric H-T. Allain, 2023. "Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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