Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma
Menée à l'aide d'un modèle murin de neuroblastome, cette étude met en évidence des mécanismes par lesquels, en favorisant la dégradation de la protéine N-Myc, un inhibiteur de la kinase Aurora A induit une régression tumorale
Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy. "Aurora-A-specific inhibitors disrupt the Aurora-A/N-Myc complex "Inhibitors trigger proteasomal degradation of N-Myc via Fbxw7 ubiquitin ligase "Inhibitors revert N-Myc-dependent gene expression in a mouse model of neuroblastoma "Inhibitors induce tumor regression and extend survival in this model