Abstract
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Aurora Kinase A
-
Aurora Kinases
-
Azepines / pharmacology*
-
Benzazepines / pharmacology*
-
Cell Cycle Proteins / physiology
-
Cell Line, Tumor
-
Cyclohexanecarboxylic Acids / pharmacology
-
F-Box Proteins / physiology
-
F-Box-WD Repeat-Containing Protein 7
-
Humans
-
Mice
-
Neuroblastoma / drug therapy*
-
Neuroblastoma / genetics
-
Neuroblastoma / pathology
-
Proteasome Endopeptidase Complex / physiology*
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / metabolism*
-
Pyrimidines / pharmacology*
-
Thiazoles / pharmacology
-
Ubiquitin-Protein Ligases / physiology
Substances
-
4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
-
Antineoplastic Agents
-
Azepines
-
Benzazepines
-
Cell Cycle Proteins
-
Cyclohexanecarboxylic Acids
-
F-Box Proteins
-
F-Box-WD Repeat-Containing Protein 7
-
FBXW7 protein, human
-
MLN 8237
-
MLN8054
-
Proto-Oncogene Proteins c-myc
-
Pyrimidines
-
Thiazoles
-
Ubiquitin-Protein Ligases
-
Aurka protein, mouse
-
Aurora Kinase A
-
Aurora Kinases
-
Protein Serine-Threonine Kinases
-
Proteasome Endopeptidase Complex