Developmentally relevant proteins contribute to chemotherapeutic resistance in neuroblastoma

Facilitators and suppressors of oncogenesis during childhood include many of the proteins and processes critical to development. Neuroblastoma is a childhood cancer that arises from the cells in the neural crest destined to populate the sympathetic nervous system. Among the arbiters and effectors of development in the neural crest are the neurotrophin receptors, Trks A, B, and C and p75NTR; the transcription factors, SIX1 and ATF5; the tyrosine kinase, ALK; and the histone modifiers, EZH2 and the HDACs. During neural development, the relative cellular expression, activation, and translocation of these proteins play important roles in determination of cell fate. We hypothesize that these proteins also play important roles in the chemoresistance of neuroblastoma.

This review explores existing evidence to implicate these developmentally relevant proteins and their temporal and spatial inconstancy in the challenge of chemoresistance of neuroblastoma.

For examination of the role of developmentally relevant mechanisms in neuroblastoma resistance to chemotherapy, searches of PubMed and ClinicalTrials.gov databases were performed using the following search terms: "neurotrophin receptor" AND "neuroblastoma"; "Trk" AND "neuroblastoma"; "p75NTR" AND "neuroblastoma"; "EZH2 inhibitors" AND "neuroblastoma"; "HDAC inhibitors" AND "neuroblastoma"; "epigenetic" AND "neuroblastoma" AND "resistance"; "ALK inhibitors" AND "neuroblastoma"; "PRMT" AND "neuroblastoma"; and "neuroblastoma differentiation" AND "therapy". Papers published within the past 10 years were considered for inclusion in discussion of response of neuroblastoma cells and clinical tumors to chemotherapeutic agents and clinical studies closed to recruitment within the past 5 years or continuing to recruit were considered for inclusion in discussion of future therapeutic approaches to clinical neuroblastoma.

A total of 317 papers were identified across all initial topics and, of these, 195 were found to be relevant to neuroblastoma therapy. Eleven papers were identified as relevant to 2 or more topics (8 papers, 2 topics; 2 papers, 3 topics; 1 paper, 6 topics), resulting in 175 unique papers identified in toto. The literature supports the notion that developmentally driven heterogeneity and changeability of specific protein expression, activation, and translocation in neuroblastomas contributes to the refractoriness of neuroblastoma to chemotherapy.

Therapeutic approaches aimed at inhibition or epigenetic modification of intratumoral neurotrophin receptors, transcription factors, tyrosine kinases, and histone modifiers are currently in clinical trials for neuroblastoma. Future efforts will require both individualization of therapy and emerging technological approaches to the heterogeneity and inconstancy of expression and processing of developmentally relevant proteins in neuroblastoma.