Journal Article

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

Yogev, Orli, Wickremesinghe, Chiharu, Xu, Yuewei, Benito, Adrian, Montoya, Alex, Chesler, Louis, Poon, Evon, da Costa, Barbara Martins, Jamin, Yann, Eckold, Clare, Want, Elizabeth J., Valbuena, Gabriel N., Keun, Hector C., Liu, Yusong, Ma, Yurui, Sikka, Arti, Balcells, Cristina, Nijhuis, Anke, Carling, David, Herendi, Lili, Gruet, Michael, Kramer, Holger

2022

Overview

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. The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 45 / 45/91 / 631/67/1059/602 / 631/67/2327 / 631/92/436/2388 / 82/58 / Cell cycle / Cell Line, Tumor / Child / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins / Metabolism / Mitochondria / multidisciplinary / N-Myc Proto-Oncogene Protein / Neoplasm Recurrence, Local / Neuroblastoma / Neuroblastoma - drug therapy / Neuroblastoma - genetics / Perturbation / Prognosis / Proteomics / Ribonucleic acid / Risk / RNA / RNA Splicing - genetics / Science / Science (multidisciplinary) / Solid tumors / Splicing / Splicing factors / Sulfonamides / Tumors / Ubiquitin / Ubiquitin-protein ligase / Xenografts / Xenotransplantation