1. Indisulam targets RNA splicing and metabolism to serve as a novel therapeutic strategy for high-risk neuroblastoma
- Author
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Lili Herendi, Hector C. Keun, Adrian Benito, Yusong Liu, Holger Kramer, Barbara Martins da Costa, David Carling, Louis Chesler, Yann Jamin, Arti Sikka, Eirini Kouloura, Gabriel N. Valbuena, Orli Yogev, Clare Eckold, Evon Poon, Elizabeth J. Want, Alex Montoya, and Anke Nijhuis
- Subjects
Cell cycle ,Biology ,Proteomics ,medicine.disease ,Transgenic Model ,chemistry.chemical_compound ,chemistry ,In vivo ,Neuroblastoma ,RNA splicing ,Metabolome ,medicine ,Cancer research ,Growth inhibition - Abstract
Neuroblastoma is the most common solid tumour in childhood 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 particularly 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 induced rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15- dependent manner. Integrative analysis of RNAseq and proteomics data highlighted a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrated metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour without relapse was observed in both xenografts and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss confirmed in vivo. Our data imply that dual targeting of metabolism and RNA splicing with anti-cancer sulphonamides such as indisulam is a promising therapeutic approach for high-risk neuroblastoma.
- Published
- 2020