Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

Monika Raab, Sven Kappel, Andrea Krämer, Mourad Sanhaji, Yves Matthess, Elisabeth Kurunci-Csacsko, Julia Calzada-Wack, Birgit Rathkolb, Jan Rozman, Thure Adler, Dirk H. Busch, Irene Esposito, Helmut Fuchs, Valérie Gailus-Durner, Martin Klingenspor, Eckhard Wolf, Nicole Sänger, Florian Prinz, Martin Hrabě de Angelis, Jost Seibler, Juping Yuan, Martin Bergmann, Rainald Knecht, Bertolt Kreft and Klaus Strebhardt ()
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Monika Raab: School of Medicine, Johann Wolfgang Goethe-University
Sven Kappel: School of Medicine, Johann Wolfgang Goethe-University
Andrea Krämer: School of Medicine, Johann Wolfgang Goethe-University
Mourad Sanhaji: School of Medicine, Johann Wolfgang Goethe-University
Yves Matthess: School of Medicine, Johann Wolfgang Goethe-University
Elisabeth Kurunci-Csacsko: School of Medicine, Johann Wolfgang Goethe-University
Julia Calzada-Wack: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Birgit Rathkolb: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Jan Rozman: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Thure Adler: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Dirk H. Busch: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München
Irene Esposito: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Helmut Fuchs: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Valérie Gailus-Durner: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Martin Klingenspor: Molecular Nutritional Medicine, Else Kröner-Fresenius Center, Technische Universität München
Eckhard Wolf: Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München
Nicole Sänger: School of Medicine, Johann Wolfgang Goethe-University
Florian Prinz: Bayer Schering Pharma AG, Global Drug Discovery, Therapeutic Research Group Oncology
Martin Hrabě de Angelis: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Jost Seibler: TaconicArtemis GmbH
Juping Yuan: School of Medicine, Johann Wolfgang Goethe-University
Martin Bergmann: Institute of Veterinary Anatomy, Histology and Embryology, University of Giessen
Rainald Knecht: Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde, UKE Hamburg
Bertolt Kreft: Bayer Schering Pharma AG, Global Drug Discovery, Therapeutic Research Group Oncology
Klaus Strebhardt: School of Medicine, Johann Wolfgang Goethe-University

Nature Communications, 2011, vol. 2, issue 1, 1-11

Abstract: Abstract High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions.

Date: 2011
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DOI: 10.1038/ncomms1395

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