Abstract

Melanoma is the deadliest form of skin cancer. While clinical developments have significantly improved patient prognosis, effective treatment is often obstructed by limited response rates, intrinsic or acquired resistance to therapy, and adverse events. Melanoma initiation and progression are associated with transcriptional reprogramming of melanocytes to a cell state that resembles the lineage from which the cells are specified during development, that is the neural crest. Convergence to a neural crest cell (NCC)-like state revealed the therapeutic potential of targeting developmental pathways for the treatment of melanoma. Neural crest cells have a unique sensitivity to metabolic dysregulation, especially nucleotide depletion. Mutations in the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) particularly affect neural crest-derived tissues and cause Miller syndrome, a genetic disorder characterized by craniofacial malformations in patients. The developmental susceptibility of the neural crest to nucleotide deficiency is conserved in melanoma and provides a metabolic vulnerability that can be exploited for therapeutic purposes. We review the current knowledge on nucleotide stress responses in neural crest and melanoma and discuss how the recent scientific advances that have improved our understanding of transcriptional regulation during nucleotide depletion can impact melanoma treatment.