Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma

Cancer Cell. 2013 Jul 8;24(1):75-89. doi: 10.1016/j.ccr.2013.05.005. Epub 2013 Jun 20.

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.

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