Targeting MYCN and ALK in resistant and relapsing neuroblastoma.

Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the oncogene, and kinase domain mutations of the anaplastic lymphoma kinase () gene. Overall survival in this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit resistance to many existing inhibitors, and no clinical therapeutics to target have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which upregulates transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of , and to identify effective inhibitors of in neuroblastoma patients.