Journal Article

RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity

Wu, Qiong, Van De Velde, Lee-Ann, Quarni, Waise, Owa, Takashi, Jin, Hongjian, Chesler, Louis, Poon, Evon, Confer, Thomas, Cortes, Andrew, Murray, Peter J., Johnson, Melissa, Easton, John, He, Liusheng, Natarajan, Sivaraman, Thorne, Rebecca, Freeman, Burgess B., Thomas, Paul G., Steele, Jacob A., Singh, Shivendra, Chen, Jiani, Murphy, Andrew J., Lockey, Timothy, Davidoff, Andrew M., Yang, Jun, Caufield, William V., Pruett-Miller, Shondra M., Fang, Jie, Woolard, Mary A., Turner, Gregory, Wang, Ruoning, Chen, Xiang, Morton, Christopher L., Connelly, Jon P., Park, Julie R.

2025

Overview

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic and mesenchymal, which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown, and how to eradicate neuroblastoma regardless of its cell state is a clinical challenge. To better understand the cellular plasticity of neuroblastoma in chemoresistance, we define the transcriptomic and epigenetic map of adrenergic and mesenchymal types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We show that cancer cells not only undergo a bidirectional switch between adrenergic and mesenchymal states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. These cell state alterations are coupled with epigenetic reprogramming and dependency switching of cell state–specific transcription factors, epigenetic modifiers, and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states. Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/2 / 13/31 / 13/44 / 38/22 / 38/23 / 38/39 / 38/91 / 42/40 / 45/15 / 45/90 / 631/67/1059/2326 / 631/67/1059/602 / 631/67/2332 / 64/60 / Animal models / Animals / Antitumor activity / Cancer therapies / Cell Line, Tumor / Cell Plasticity - drug effects / Cell Plasticity - genetics / Cell Plasticity - immunology / Cells / Chemoresistance / Cytotoxicity / Drug dosages / Drug resistance / Epigenesis, Genetic - drug effects / Epigenetics / Gene Expression Regulation, Neoplastic - drug effects / Genes / Humanities and Social Sciences / Humans / Immunity (Disease) / Immunity, Innate - drug effects / Immunotherapy / Immunotherapy - methods / Innate immunity / Killer Cells, Natural - drug effects / Killer Cells, Natural - immunology / Kinases / Medical innovations / Medical prognosis / Mice / Mice, Transgenic / multidisciplinary / Mutation / Natural killer cells / Neural crest / Neuroblastoma / Neuroblastoma - drug therapy / Neuroblastoma - genetics / Neuroblastoma - immunology / Neuroblastoma - pathology / Neuroblasts / Pediatrics / Plastic foam / Plastic properties / Plasticity / RNA Splicing - drug effects / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Therapy / Transcription factors / Transcriptomics / Tumor cells / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / Ultrasonic imaging