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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
PRECLINICAL STUDIES

Summary

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.

Keywords

Inhibitor BRCA2 Aurora kinase Breast cancer p53 

Notes

Acknowledgements

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.

References

  1. 1.
    Gautschi O, Mack PC, Davies AM, Lara PN Jr, Gandara DR (2006) Aurora kinase inhibitors: a new class of targeted drugs in cancer. Clin Lung Cancer 8:93–98PubMedCrossRefGoogle Scholar
  2. 2.
    Matthews N, Visintin C, Hartzoulakis B, Jarvis A, Selwood DL (2006) Aurora A and B kinases as targets for cancer: will they be selective for tumors? Expert Rev Anticancer Ther 6:109–120PubMedCrossRefGoogle Scholar
  3. 3.
    Meraldi P, Honda R, Nigg EA (2004) Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev 14:29–36PubMedCrossRefGoogle Scholar
  4. 4.
    Gassmann R, Carvalho A, Henzing AJ, Ruchaud S, Hudson DF, Honda R, Nigg EA, Gerloff DL, Earnshaw WC (2004) Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J Cell Biol 166:179–191PubMedCrossRefGoogle Scholar
  5. 5.
    Adams RR, Carmena M, Earnshaw WC (2001) Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 11:49–54PubMedCrossRefGoogle Scholar
  6. 6.
    Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ (2003) Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res 9:1420–1426PubMedGoogle Scholar
  7. 7.
    Jeng YM, Peng SY, Lin CY, Hsu HC (2004) Overexpression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res 10:2065–2071PubMedCrossRefGoogle Scholar
  8. 8.
    Sakakura C, Hagiwara A, Yasuoka R, Fujita Y, Nakanishi M, Masuda K, Shimomura K, Nakamura Y, Inazawa J, Abe T, Yamagishi H (2001) Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer 84:824–831PubMedCrossRefGoogle Scholar
  9. 9.
    Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193PubMedCrossRefGoogle Scholar
  10. 10.
    Sen S, Zhou H, White RA (1997) A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 14:2195–2200PubMedCrossRefGoogle Scholar
  11. 11.
    Katayama H, Ota T, Jisaki F, Ueda Y, Tanaka T, Odashima S, Suzuki F, Terada Y, Tatsuka M (1999) Mitotic kinase expression and colorectal cancer progression. J Natl Cancer Inst 91:1160–1162PubMedCrossRefGoogle Scholar
  12. 12.
    Sorrentino R, Libertini S, Pallante PL, Troncone G, Palombini L, Bavetsias V, Spalletti-Cernia D, Laccetti P, Linardopoulos S, Chieffi P, Fusco A, Portella G (2005) Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 90:928–935PubMedCrossRefGoogle Scholar
  13. 13.
    Araki K, Nozaki K, Ueba T, Tatsuka M, Hashimoto N (2004) High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol 67:53–64PubMedCrossRefGoogle Scholar
  14. 14.
    Tatsuka M, Katayama H, Ota T, Tanaka T, Odashima S, Suzuki F, Terada Y (1998) Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 58:4811–4816PubMedGoogle Scholar
  15. 15.
    Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS (2003) Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161:267–280PubMedCrossRefGoogle Scholar
  16. 16.
    Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, Heckel A, van Meel J, Rieder CL, Peters JM (2003) The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 161:281–294PubMedCrossRefGoogle Scholar
  17. 17.
    Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM (2004) VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10:262–267PubMedCrossRefGoogle Scholar
  18. 18.
    Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, Keen NJ, Taylor SS (2006) Validating Aurora B as an anti-cancer drug target. J Cell Sci 119:3664–3675PubMedCrossRefGoogle Scholar
  19. 19.
    Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, Foster JR, Brady MC, Bigley A, Brown E, Byth KF, Barrass NC, Mundt KE, Foote KM, Heron NM, Jung FH, Mortlock AA, Boyle FT, Green S (2007) AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 13:3682–3688PubMedCrossRefGoogle Scholar
  20. 20.
    Emanuel S, Rugg CA, Gruninger RH, Lin R, Fuentes-Pesquera A, Connolly PJ, Wetter SK, Hollister B, Kruger WW, Napier C, Jolliffe L, Middleton SA (2005) The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res 65:9038–9046PubMedCrossRefGoogle Scholar
  21. 21.
    Bodvarsdottir SK, Hilmarsdottir H, Birgisdottir V, Steinarsdottir M, Jonasson JG, Eyfjord JE (2007) Aurora-A amplification associated with BRCA2 mutation in breast tumours. Cancer Lett 248:96–102PubMedCrossRefGoogle Scholar
  22. 22.
    Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193PubMedCrossRefGoogle Scholar
  23. 23.
    Krystyniak A, Garcia-Echeverria C, Prigent C, Ferrari S (2006) Inhibition of Aurora A in response to DNA damage. Oncogene 25:338–348PubMedGoogle Scholar
  24. 24.
    Anand S, Penrhyn-Lowe S, Venkitaraman AR (2003) AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to taxol. Cancer Cell 3:51–62PubMedCrossRefGoogle Scholar
  25. 25.
    Daniels MJ, Wang Y, Lee M, Venkitaraman AR (2004) Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306:876–879PubMedCrossRefGoogle Scholar
  26. 26.
    Vidarsdottir L, Bodvarsdottir SK, Hilmarsdottir H, Tryggvadottir L, Eyfjord JE (2007) Breast cancer risk associated with AURKA 91T –>A polymorphism in relation to BRCA mutations. Cancer Lett 250:206–212PubMedCrossRefGoogle Scholar
  27. 27.
    Yang G, Chang B, Yang F, Guo X, Cai KQ, Xiao XS, Wang H, Sen S, Hung MC, Mills GB, Chang S, Multani AS, Mercado-Uribe I, Liu J (2010) Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2. Clin Cancer Res 16:3171–3181Google Scholar
  28. 28.
    Sourisseau T, Maniotis D, McCarthy A, Tang C, Lord CJ, Ashworth A, Linardopoulos S (2010) Aurora-A expressing tumour cells are deficient for homology-directed DNA double strand-break repair and sensitive to PARP inhibition. EMBO Mol Med 2:130–142PubMedCrossRefGoogle Scholar
  29. 29.
    Gizatullin F, Yao Y, Kung V, Harding MW, Loda M, Shapiro GI (2006) The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function. Cancer Res 66:7668–7677PubMedCrossRefGoogle Scholar
  30. 30.
    Dreier MR, Grabovich AZ, Katusin JD, Taylor WR (2009) Short and long-term tumor cell responses to Aurora kinase inhibitors. Exp Cell Res 315:1085–1099PubMedCrossRefGoogle Scholar
  31. 31.
    Li M, Jung A, Ganswindt U, Marini P, Friedl A, Daniel PT, Lauber K, Jendrossek V, Belka C (2010) Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways. Biochem Pharmacol 79:122–129Google Scholar
  32. 32.
    Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H (2007) A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. Mol Cancer Ther 6:1851–1857PubMedCrossRefGoogle Scholar
  33. 33.
    Rubner Fridriksdottir AJ, Gudjonsson T, Halldorsson T, Bjornsson J, Steinarsdottir M, Johannsson OT, Ogmundsdottir HM (2005) Establishment of three human breast epithelial cell lines derived from carriers of the 999del5 BRCA2 Icelandic founder mutation. In Vitro Cell Dev Biol Anim 41:337–342PubMedCrossRefGoogle Scholar
  34. 34.
    Gudjonsson T, Villadsen R, Nielsen HL, Ronnov-Jessen L, Bissell MJ, Petersen OW (2002) Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties. Genes Dev 16:693–706PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang H, Jin Y, Chen X, Jin C, Law S, Tsao SW, Kwong YL (2007) Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation. Cancer Lett 245:184–194PubMedCrossRefGoogle Scholar
  36. 36.
    Lewis CM, Herbert BS, Bu D, Halloway S, Beck A, Shadeo A, Zhang C, Ashfaq R, Shay JW, Euhus DM (2006) Telomerase immortalization of human mammary epithelial cells derived from a BRCA2 mutation carrier. Breast Cancer Res Treat 99:103–115PubMedCrossRefGoogle Scholar

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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