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

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

doi:10.1016/j.ccr.2013.05.005

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.

Authors

Affiliations

¹ Comprehensive Cancer Center Mainfranken and Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
² Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
³ CCU Pediatric Oncology, DKFZ and Department of Pediatrics 3, University Hospital Heidelberg, Germany, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
⁴ Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str. 2, 35037 Marburg, Germany.
⁵ Division of Radiotherapy and Imaging, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
⁶ Division of Pathology, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
⁷ University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.

^# Contributed equally.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding