Advances in Targeting Growth Factor Signalling in Neuroblastoma and Overcoming Drug Resistance

Neuroblastoma is an embryonal tumour that arises from the malignant transformation of neural crest cells and remains one of the deadliest malignancies in children under five. Neural crest development is regulated by dynamic switches in transcriptional programmes, guided by a variety of growth factors. Due to its developmental origin, neuroblastoma is unique in that these tumours often retain overactivation of growth factor signalling, which can be targeted by receptor tyrosine kinase (RTK) inhibitors. However, mutations in kinases, except for ALK, are extremely rare in neuroblastoma. Furthermore, the high degree of intratumoural heterogeneity often renders RTK inhibition ineffective as a monotherapy. For high-risk tumours, which lack effective treatment options, there remains an unmet need for targeted therapies. This review summarises the roles of growth factor receptors in neural crest and neuroblastoma development in light of recent single-cell studies. We provide a systematic overview of RTK inhibitors that can target growth factor signalling in neuroblastoma and detail their current status in clinical development. We also explore the role of intratumoural heterogeneity in resistance to RTK inhibitors, focusing on the adrenergic-to-mesenchymal transition, which drives a switch in growth factor receptor expression. Finally, we discuss strategies to overcome RTK inhibitor resistance by targeting neuroblastoma cell plasticity, disrupting downstream signalling pathways, or inhibiting escape mechanisms from cell death. This review provides a theoretical basis for developing novel combination therapies incorporating RTK inhibitors.