Fig. 9: Models for neuroblastoma cell plasticity and the working mechanism of indisulam.
From: RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity
a Schwann cell precursors from neural crest cells could differentiate to distinct lineages, including neuroblasts and chromaffin cells that are presumed to be cells of origin of neuroblastoma. NCC, neural crest cell. SCP, Schwann cell precursors. b Neuroblastoma cells have multiple cell states that are potentially able to interconvert. These cell states are determined by lineage–specific master TFs or CRC TFs. ADRN, adrenergic. MES, mesenchymal. Melano, melanocytic. c The mechanism of action of indisulam. d The anticancer mechanism for the combination of indisulam with anti-GD2 immunotherapy. Indisulam degrades RBM39 in neuroblastoma cells, leading to cell death due to splicing defects (top). Indisulam also directly activates NK cells, leading to NK cell-mediated killing (middle). At the same time, indisulam induced an inflamed state of neuroblastoma cells, causing immune cell infiltration. When GD2 immunotherapy is applied, NK cells elicit antibody-dependent cellular cytotoxicity (ADCC) to kill neuroblastoma cells (bottom). All three mechanisms together lead to a durable complete response.
