Eradicating neuroblastomas by an RBM39 degrader in combination with anti-GD2 immunotherapy regardless of cancer cell state alterations [CUT&Tag]

The lineage plasticity of neuroblastoma cells is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which presumably contributes to therapy resistance. However, how the neuroblastoma cells switch their cell states during therapy remains largely unknown and how to eradicate neuroblastoma cells regardless of their cell state alterations is a clinical challenge. By using four distinct human and murine neuroblastoma models treated with indisulam, a molecular glue drug serving as a selective RBM39 degrader, we show that cancer cells not only can undergo bidirectional switch of ADRN and MES cell states, but also can acquire additional cell states of melanoma and Schwann cell progenitors, reminiscent of the cellular pliancy of neural crest cells. The lineage alterations of neuroblastoma cells are coupled with epigenetic changes and dependency switch of lineage-specific transcription factors. Nevertheless, indisulam treatment induces an inflamed tumor microenvironment leading to an immune cell infiltration. The combination of indisulam with anti-GD2 monoclonal immunotherapy results in a durable complete response in transgenic neuroblastoma models driven by MYCN and ALK mutant oncogenes, providing a therapeutic rationale to eradicate tumor cells even when they acquire alternative cell lineage(s) in response to treatment.