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Combined inhibition of Aurora-A and ATR kinase results in regression of MYCN-amplified neuroblastoma.
Roeschert, Isabelle; Poon, Evon; Henssen, Anton G; Garcia, Heathcliff Dorado; Gatti, Marco; Giansanti, Celeste; Jamin, Yann; Ade, Carsten P; Gallant, Peter; Schülein-Völk, Christina; Beli, Petra; Richards, Mark; Rosenfeldt, Mathias; Altmeyer, Matthias; Anderson, John; Eggert, Angelika; Dobbelstein, Matthias; Bayliss, Richard; Chesler, Louis; Büchel, Gabriele; Eilers, Martin.
Afiliação
  • Roeschert I; Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • Poon E; 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.
  • Henssen AG; Experimental and Clinical Research Center, Max Delbrück Center and Charité Berlin, Lindenberger Weg 80, 13125 Berlin, Germany.
  • Garcia HD; Experimental and Clinical Research Center, Max Delbrück Center and Charité Berlin, Lindenberger Weg 80, 13125 Berlin, Germany.
  • Gatti M; Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstraße 190, 8057 Zurich, Switzerland.
  • Giansanti C; Institute of Molecular Oncology, Center of Molecular Biosciences, University of Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany.
  • Jamin Y; Divisions of Radiotherapy and Imaging, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
  • Ade CP; Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • Gallant P; Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • Schülein-Völk C; Theodor Boveri Institute, Core Unit High-Content Microscopy, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • Beli P; Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany.
  • Richards M; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
  • Rosenfeldt M; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
  • Altmeyer M; Department of Molecular Mechanisms of Disease, University of Zurich, Winterthurerstraße 190, 8057 Zurich, Switzerland.
  • Anderson J; UCL Great Ormond Street Institute of Child Health, 30 Guilford Street London WC1N 1EH, UK.
  • Eggert A; Experimental and Clinical Research Center, Max Delbrück Center and Charité Berlin, Lindenberger Weg 80, 13125 Berlin, Germany.
  • Dobbelstein M; Institute of Molecular Oncology, Center of Molecular Biosciences, University of Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany.
  • Bayliss R; Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
  • Chesler L; 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.
  • Büchel G; Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • Eilers M; Mildred Scheel Early Career Center, University Hospital Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
Nat Cancer ; 2(3): 312-326, 2021 03.
Article em En | MEDLINE | ID: mdl-33768209
ABSTRACT
Amplification of MYCN is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription-replication conflicts is an effective therapy for MYCN-driven neuroblastoma (141 words).
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aurora Quinase A / Neuroblastoma Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aurora Quinase A / Neuroblastoma Idioma: En Ano de publicação: 2021 Tipo de documento: Article