title: Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma.
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.
authors.affiliation: Comprehensive Cancer Center Mainfranken and Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Brockmann
authors.affiliation: 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.
authors.forename: Evon
authors.initials: E
authors.lastname: Poon
authors.affiliation: 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.
authors.forename: Teeara
authors.initials: T
authors.lastname: Berry
authors.affiliation: Comprehensive Cancer Center Mainfranken and Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Carstensen
authors.affiliation: CCU Pediatric Oncology, DKFZ and Department of Pediatrics 3, University Hospital Heidelberg, Germany, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str. 2, 35037 Marburg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Rycak
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.affiliation: Division of Pathology, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.affiliation: CCU Pediatric Oncology, DKFZ and Department of Pediatrics 3, University Hospital Heidelberg, Germany, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.affiliation: University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: 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.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: Comprehensive Cancer Center Mainfranken and Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D044783:F-Box Proteins / Q000502:physiology; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
chemical_list: C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D000970:Antineoplastic Agents; D001381:Azepines; D001552:Benzazepines; D018797:Cell Cycle Proteins; D003509:Cyclohexanecarboxylic Acids; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C550258:MLN 8237; C518940:MLN8054; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D013844:Thiazoles; D044767:Ubiquitin-Protein Ligases; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex