Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Aurora-kinase inhibitors as anticancer agents

Nature Reviews Cancer volume 4, pages 927–936 (2004)Cite this article

Key Points

  • Human tumour cells are typically aneuploid, with both changes in chromosome number and structure, due to chromosome instability. One source of this instability is mitosis, during which errors in chromosome segregation can lead to gains or losses of chromosomes.

  • Members of the Aurora family of protein kinases are required for multiple aspects of mitosis. Aurora-A localizes to centrosomes/spindle poles and is required for spindle assembly, whereas Aurora-B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation and cytokinesis.

  • Aurora-A and -B are both overexpressed in a wide range of different human tumours. Aurora-A has also been shown to be an oncogene in in vitro transformation assays.

  • Three Aurora-kinase inhibitors have recently been described — ZM447439, Hesperadin and VX-680. All three induce similar phenotypes in cell-based assays and, interestingly, VX-680 shows antitumour activity in rodent xenograft models.

  • In mitosis, ZM447439 and Hesperadin both inhibit chromosome alignment and spindle-checkpoint function. RNAi-based experiments and overexpression of Aurora-kinase mutants indicate that these phenotypes seem to be due to inhibition of Aurora-B, not Aurora-A.

  • These drugs are not 'antimitotic' agents in that they do not directly inhibit cell-cycle progression. Rather, following an aberrant mitosis, activation of the p53-dependent post-mitotic checkpoint induces 'pseudo G1' cell-cycle arrest.

  • Although Aurora-A has received most of the attention so far in terms of a link with human cancer, Aurora-B might be the more suitable anticancer drug target, simply because inhibition of Aurora-B rapidly results in a catastrophic mitosis, which leads to cell death.

Abstract

Errors in mitosis can provide a source of the genomic instability that is typically associated with tumorigenesis. Many mitotic regulators are aberrantly expressed in tumour cells. These proteins could therefore make useful therapeutic targets. The kinases Aurora-A, -B and -C represent a family of such targets and several small-molecule inhibitors have been shown to block their function. Not only have these inhibitors advanced our understanding of mitosis, but, importantly, their in vivo antitumour activity has recently been reported. What have these studies taught us about the therapeutic potential of inhibiting this family of kinases?

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Humans express three Aurora kinases.
Figure 2: Aurora-A and -B localize to key mitotic structures.
Figure 3: Accurate chromosome segregation requires chromosome bi-orientation.
Figure 4: Aurora-B resolves syntelic orientations.

Similar content being viewed by others

References

  1. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Adams, R. R., Carmena, M. & Earnshaw, W. C. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol. 11, 49–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Carmena, M. & Earnshaw, W. C. The cellular geography of aurora kinases. Nature Rev. Mol. Cell Biol. 4, 842–854 (2003).

    Article  CAS  Google Scholar 

  4. Nigg, E. A. Mitotic kinases as regulators of cell division and its checkpoints. Nature Rev. Mol. Cell Biol. 2, 21–32 (2001).

    Article  CAS  Google Scholar 

  5. Bischoff, J. R. et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17, 3052–3065 (1998). Describes the identification of the mammalian Aurora-A and -B proteins, demonstrates that both are overexpressed in human tumours and that Aurora-A is an oncogene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sen, S., Zhou, H. & White, R. A. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 14, 2195–2200 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Warner, S. L., Bearss, D. J., Han, H. & Von Hoff, D. D. Targeting Aurora-2 kinase in cancer. Mol. Cancer Ther. 2, 589–595 (2003).

    CAS  PubMed  Google Scholar 

  8. Hauf, S. et al. 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, 281–294 (2003). First description of Hesperadin, including a careful analysis showing how inhibition of Aurora-kinase activity in human cells results in syntelic orientation of chromosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ditchfield, C. et al. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J. Cell Biol. 161, 267–280 (2003). First description of ZM447439, including a careful analysis showing how inhibition of Aurora-kinase activity in human cells compromises the spindle checkpoint and induces endoreduplication in p53-deficient cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Harrington, E. A. et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med. 10, 262–267 (2004). First description of VX-680, including a demonstration of the antitumour activity of an Aurora-kinase inhibitor in rodent xenograft models.

    Article  CAS  PubMed  Google Scholar 

  11. Hirota, T. et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 114, 585–598 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Anand, S., PenrhynLowe, S. & Venkitaraman, A. R. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3, 51–62 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Meraldi, P., Honda, R. & Nigg, E. A. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J. 21, 483–492 (2002). Many tumour cells, including ones with p53 deficiencies, have abnormal numbers of centrosomes. This paper shows that this is not necessarily because the mechanisms that control centrosome amplification are dysregulated, but because cytokinesis often fails when mitotic regulators, including Aurora-A, are overexpressed, leading to a tetraploid cell with four centrosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kimura, M., Matsuda, Y., Yoshioka, T. & Okano, Y. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J. Biol. Chem. 274, 7334–7340 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Li, X. et al. Direct association with inner centromere protein (INCENP) activates the novel chromosomal passenger protein, Aurora-C. J. Biol. Chem. 16 Aug 2004 (doi: 10.1074/jbc.M403029200).

    Article  CAS  Google Scholar 

  16. Meraldi, P., Honda, R. & Nigg, E. A. Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr. Opin. Genet. Dev. 14, 29–36 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Gassmann, R. et al. Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J. Cell Biol. 166, 179–191 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gritsko, T. M. et al. Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin. Cancer Res. 9, 1420–1426 (2003).

    CAS  PubMed  Google Scholar 

  19. Katayama, H. et al. Mitotic kinase expression and colorectal cancer progression. J. Natl Cancer Inst. 91, 1160–1162 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Li, D. et al. Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin. Cancer Res.. 9, 991–997 (2003).

    CAS  PubMed  Google Scholar 

  21. Miyoshi, Y., Iwao, K., Egawa, C. & Noguchi, S. Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int. J. Cancer 92, 370–373 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Sakakura, C. et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br. J. Cancer 84, 824–831 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sen, S. et al. Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J. Natl Cancer Inst. 94, 1320–1329 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Margolis, R. L., Lohez, O. D. & Andreassen, P. R. G1 tetraploidy checkpoint and the suppression of tumorigenesis. J. Cell. Biochem. 88, 673–683 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Tanaka, T. U. et al. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108, 317–329 (2002). Demonstrates that the budding yeast Aurora kinase Ipl1 destabilizes kinetochore–microtubule interactions that do not yield tension across the centromere.

    Article  CAS  PubMed  Google Scholar 

  26. Nicklas, R. B. How cells get the right chromosomes. Science 275, 632–637 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Musacchio, A. & Hardwick, K. G. The spindle checkpoint: structural insights into dynamic signalling. Nature Rev. Mol. Cell Biol. 3, 731–741 (2002).

    Article  CAS  Google Scholar 

  28. Taylor, S. S., Scott, M. I. & Holland, A. J. The spindle checkpoint: a quality control mechanism which ensures accurate chromosome segregation. Chromosome Res. 12, 599–616 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Biggins, S. & Murray, A. W. The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the spindle checkpoint. Genes Dev. 15, 3118–3129 (2001). Demonstrates that the budding yeast Aurora kinase Ipl1 activates the spindle checkpoint in the absence of tension across the centromere.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roghi, C. et al. The Xenopus protein kinase pEg2 associates with the centrosome in a cell cycle-dependent manner, binds to the spindle microtubules and is involved in bipolar mitotic spindle assembly. J. Cell Sci. 111, 557–572 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Glover, D. M., Leibowitz, M. H., McLean, D. A. & Parry, H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81, 95–105 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Marumoto, T. et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J. Biol. Chem. 278, 51786–51795 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. MurataHori, M. & Wang, Y. L. The kinase activity of aurora B is required for kinetochore-microtubule interactions during mitosis. Curr. Biol. 12, 894–899 (2002).

    Article  CAS  Google Scholar 

  34. Kallio, M. J., McCleland, M. L., Stukenberg, P. T. & Gorbsky, G. J. Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis. Curr. Biol. 12, 900–905 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Carvalho, A., Carmena, M., Sambade, C., Earnshaw, W. C. & Wheatley, S. P. Survivin is required for stable checkpoint activation in taxol-treated HeLa cells. J. Cell Sci. 116, 14–98 (2003).

    Article  CAS  Google Scholar 

  36. Lens, S. M. et al. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J. 22, 2934–2947 (2003). References 35 and 36 show that repression of the Aurora-B binding partner survivin results in a similar phenotype to that induced by Hesperadin and ZM447439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Johnson, V. L., Scott, M. I., Holt, S. V., Hussein, D. & Taylor, S. S. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J. Cell Sci. 117, 8–89 (2004).

    Google Scholar 

  38. Dutertre, S. & Prigent, C. Aurora-A overexpression leads to override of the microtubule-kinetochore attachment checkpoint. Mol. Interv. 3, 127–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Adams, R. R., Maiato, H., Earnshaw, W. C. & Carmena, M. Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. J. Cell Biol. 153, 865–880 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Giet, R. & Glover, D. M. Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J. Cell Biol. 152, 669–682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Terada, Y. et al. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J. 17, 667–676 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hamada, M. et al. Aurora2/BTAK/STK15 is involved in cell cycle checkpoint and cell survival of aggressive non-Hodgkin's lymphoma. Br. J. Haematol. 121, 439–447 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Zhou, H. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genet. 20, 189–193 (1998). Reports that overexpression of Aurora-A in mouse fibroblasts induces centrosome duplication–distribution abnormalities, aneuploidy and transformation. Furthermore, overexpression of Aurora-A in human breast epithelial cells revealed similar centrosome abnormalities, as well as induction of aneuploidy.

    Article  CAS  PubMed  Google Scholar 

  44. EwartToland, A. et al. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nature Genet. 34, 403–412 (2003). Quantitative trait loci mapping of a locus that confers susceptibility to skin tumours in mice identifies Aurora-A. Comparative analysis of human samples identifies a polymorphism in Aurora-A.

    Article  CAS  Google Scholar 

  45. Katayama, H. et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nature Genet. 36, 55–62 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Walter, A. O., Seghezzi, W., Korver, W., Sheung, J. & Lees, E. The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. Oncogene 19, 4906–4916 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Sitnicka, E. et al. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 17, 463–472 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Mayer, T. U. et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971–974 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Sakowicz, R. et al. Antitumor activity of a kinesin inhibitor. Cancer Res. 64, 3276–3280 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Giet, R. et al. Drosophila Aurora A kinase is required to localize D-TACC to centrosomes and to regulate astral microtubules. J. Cell Biol. 156, 437–451 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Conte, N. et al. TACC1–chTOG–Aurora A protein complex in breast cancer. Oncogene 22, 8102–8116 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Delaval, B. et al. Aurora B–TACC1 protein complex in cytokinesis. Oncogene 23, 4516–4522 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank S. Green, D. Johnstone, D. Roberts, H. Robson and E. Brown (all from AstraZeneca) for helpful comments on the manuscript. We would also like to thank C. Ditchfield and the AstraZeneca Bioinformatics group for sharing unpublished data.

Author information

Authors and Affiliations

  1. Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Cheshire, SK10 4TG, UK

    Nicholas Keen

  2. Faculty of Life Sciences, University of Manchester, M13 9PT, UK

    Stephen Taylor

Authors
  1. Nicholas Keen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas Keen.

Ethics declarations

Competing interests

Nicholas Keen is an employee of AstraZeneca UK Ltd, part of the AstraZeneca group of companies, and is also a shareholder in the holding company Astrazeneca PLC.

Related links

Related links

DATABASES

Entrez Gene

Aurora-A

Aurora-B

Aurora-C

borealin

BUB1

BUBR1

FLT3

INCENP

p53

survivin

TPX2

National Cancer Institute

breast cancer

colon cancer

gastric cancer

ovarian cancer

pancreatic cancer

FURTHER INFORMATION

University of Arizona Cell Cycle and Mitosis Tutorial

Glossary

MICROTUBULE

A hollow tube made of α- and β-tubulin subunits, which forms part of the interphase cytoskeleton and the mitotic spindle.

CHECKPOINT

A surveillance mechanism that prevents cell-cycle progression in response to events that, if uncorrected, can result in genome damage.

CENTROSOME

Microtubule-organizing centre typically found at the centre of the cell and from which the interphase microtubule cytoskeleton radiates. Following duplication in S phase, the two centrosomes form the spindle poles in mitosis.

SPINDLE CHECKPOINT

A cell-cycle checkpoint that prevents anaphase until all the chromosomes are correctly bi-oriented on the mitotic-spindle apparatus.

CYTOKINESIS

The process of cell division, which is normally coupled to mitosis.

CHROMOSOME PASSENGER

A protein that localizes to the chromosomes, and more specifically the centromeres, in the early phases of mitosis, but then relocates to the spindle midzone following anaphase onset.

ANAPHASE

Movement of the sister chromatids to opposite spindle poles following loss of sister-chromatid cohesion at the metaphase–anaphase transition.

CENTROMERE

A specialized region of the chromosome, typically seen as a primary constriction, which assembles the two kinetochores and maintains sister-chromatid cohesion until the onset of anaphase.

KINETOCHORE

Proteinacious structure that assembles at the centromere of each sister chromatid. During mitosis, kinetochores attach and move chromosomes on the microtubule spindle. When unattached, they activate the spindle checkpoint.

POLYPLOID

Most normal cells have a 2N (diploid) DNA content. A polyploid cell carries multiple chromosomes, resulting from chromosome replication without nuclear or cell division.

ENDOREDUPLICATION

The accumulation of multiple copies of a cell's DNA, which results when replication is not coordinated to the cell cycle.

PACLITAXEL

A naturally occurring compound, originally purified from the pacific yew tree, that stabilizes microtubules and has antitumour activity.

NOCODAZOLE

A microtubule toxin that prevents microtubule assembly.

SECOND- OR THIRD-GENERATION INHIBITORS

Usually describes drugs that were modified from an original class of compounds, using feedback from clinical studies to address any toxicity issues or to optimize biological properties.

THERAPEUTIC INDEX

The therapeutic index is a comparison of the amount of a medication that causes the therapeutic effect to the amount that causes toxic effects. A drug with a high therapeutic index produces its therapeutic effects at significantly lower doses than those where limiting toxicology is apparent.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keen, N., Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4, 927–936 (2004). https://doi.org/10.1038/nrc1502

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1502

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing