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

• Published in: Nature communications 2011-07, Vol.2 (1), p.395, Article 395
• Main Authors: Raab, Monika, Kappel, Sven, Krämer, Andrea, Sanhaji, Mourad, Matthess, Yves, Kurunci-Csacsko, Elisabeth, Calzada-Wack, Julia, Rathkolb, Birgit, Rozman, Jan, Adler, Thure, Busch, Dirk H., Esposito, Irene, Fuchs, Helmut, Gailus-Durner, Valérie, Klingenspor, Martin, Wolf, Eckhard, Sänger, Nicole, Prinz, Florian, Angelis, Martin Hrabě de, Seibler, Jost, Yuan, Juping, Bergmann, Martin, Knecht, Rainald, Kreft, Bertolt, Strebhardt, Klaus
• Format: Article
• Language: English
• Subjects: 631/1647/1511; 631/337/176/2016; 631/337/505; 692/699/67; Animals; Antineoplastic Agents - toxicity; Apoptosis - genetics; Blotting, Northern; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cells, Cultured; DNA Primers - genetics; Drug Evaluation, Preclinical; Flow Cytometry; Fluorescent Antibody Technique; Gene Dosage - genetics; Gene Knockdown Techniques; Genetic Engineering - methods; Humanities and Social Sciences; Humans; Mice; Mice, Transgenic; multidisciplinary; Neoplasms - drug therapy; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference - drug effects; Science; Science (multidisciplinary); Toxicity Tests - methods; Transfection
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms1395

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. Polo-like kinase 1 is a key regulator of mitosis and is a candidate for drug development to treat cancer. Here, reduced expression of polo-like kinase 1 in adult mice has a minor impact on animal physiology, suggesting that polo-like kinase 1 inhibitors may be useful in the killing of tumour cells while sparing normal cells.