Investigational New Drugs

, Volume 30, Issue 2, pp 425–434 | Cite as

Sensitivity of BRCA2 mutated human cell lines to Aurora kinase inhibition

  • Linda Vidarsdottir
  • Gudridur Steingrimsdottir
  • Sigridur Klara Bodvarsdottir
  • Helga Margret Ogmundsdottir
  • Jorunn Erla EyfjordEmail author


Aurora kinases play a vital part in successful mitosis and cell division. Aberrant Aurora-A and -B expression is commonly seen in various types of tumors. Small molecule Aurora inhibitors have already entered clinical trials. Aurora-A amplification has been shown to be associated with breast tumors from BRCA2-mutation carriers and such patients might therefore be candidates for treatment with Aurora kinase inhibitors. There is a need to identify markers that can predict sensitivity to Aurora inhibition. In this study sensitivity to the inhibitor ZM447439 was tested on a panel of 15 non-malignant and malignant epithelial cell lines that differed with respect to BRCA2 and p53 status and related to level of Aurora kinase expression. The IC50 value for cell survival ranged from 1.9–8.1 μM and was not related to presence or absence of BRCA2 mutation. The levels of Aurora-A and -B expression correlated with each other but sensitivity towards ZM447439 did not correlate with levels of Aurora-A and -B mRNA expression, alone. Cells treated with the Aurora kinase inhibitor completed mitosis but cytokinesis was inhibited resulting in polyploidy and multinucleation. Different levels of polyploidy could not be fully explained by defects in p53. Only cell lines with a combination of high Aurora-A and -B expression, BRCA2 mutation and p53 defects showed more sensitivity towards Aurora inhibition than other cell lines. In conclusion, BRCA2-mutated cells showed variable sensitivity towards Aurora kinase inhibition. The level of sensitivity could not be predicted by Aurora expression levels alone but BRCA2 mutated tumors with high Aurora expression and non-functional p53 are likely candidates for treatment with Aurora inhibitors.


Inhibitor BRCA2 Aurora kinase Breast cancer p53 



The authors thank Margrét Steinarsdóttir at the Chromosome Laboratory, Department of Genetics and Molecular Medicine at Landspitali National University Hospital for cytogenetic analysis and Cheryl M. Lewis and David M. Euhus (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA) for providing 348T, 348KT, 2980T, 2981T, 1585T, 1585KT and 3736T cell lines (Hamond Center for Therapeutic Oncology Research and Department of Surgery, University of Texas, Southwestern Medical Center, Dallas, USA). This work was supported by the Icelandic Research Fund for graduate students (L. Vidarsdottir), the University of Iceland Research Fund, Gongum saman and the Icelandic Science Foundation (RANNIS).

Conflict of interest

The authors declare that there are no conflicts of interest.


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Linda Vidarsdottir
    • 1
  • Gudridur Steingrimsdottir
    • 1
    • 2
  • Sigridur Klara Bodvarsdottir
    • 1
  • Helga Margret Ogmundsdottir
    • 1
  • Jorunn Erla Eyfjord
    • 1
    • 3
    Email author
  1. 1.Cancer Research Laboratory, Biomedical Center, Faculty of MedicineUniversity of IcelandReykjavikIceland
  2. 2.Faculty of PharmacyUniversity of IcelandReykjavikIceland
  3. 3.Cancer Research Laboratory, Biomedical Center, Faculty of MedicineUniversity of IcelandReykjavikIceland

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