Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma

详细信息    查看全文

• 作者：Markus Brockmann ; Evon Poon ; Teeara Berry ; Anne Carstensen ; Hedwig?E. Deubzer ; Lukas Rycak ; Yann Jamin ; Khin Thway ; Simon?P. Robinson ; Frederik Roels ; Olaf Witt ; Matthias Fischer ; Louis Chesler ; Martin Eilers
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：8 July, 2013
• 年：2013
• 卷：24
• 期：1
• 页码：75-89
• 全文大小：2665 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferencesml version=""1.0"" encoding=""UTF-8""?>

Summary

Amplification of <em>MYCNem> is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by <em>MYCNem>, 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 <em>MYCNem>-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.