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  • Review Article
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Shared and separate functions of polo-like kinases and aurora kinases in cancer

Nature Reviews Cancer volume 10, pages 825–841 (2010)Cite this article

Subjects

Key Points

  • The polo-like kinases 1–5 (PLK1–5), and aurora kinases, aurora kinase A, aurora kinase B and aurora kinase C have essential roles during cell division, and a large number of inhibitors for these kinases are currently being evaluated as anticancer drugs in Phase I and Phase II clinical trials.

  • Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles.

  • The efficacy of polo-like kinase and aurora kinase inhibitors probably primarily depends on their capacity to severely disrupt normal cell division, implying a limited tumour specificity of these types of drugs.

  • It is unclear whether PLK1 and the aurora kinases have oncogenic or tumour suppressor activity when deregulated. However, the increased cancer incidence in heterozygous mice suggests a role for them as tumour suppressors, probably through the prevention of chromosome instability.

  • PLK1 and the aurora kinases co-regulate multiple processes in the dividing cell, such as entry into mitosis, mitotic spindle formation, sister chromatid resolution, chromosome–spindle connections and cytokinesis. Although some overlap in clinical performance can be expected of PLK1 and aurora kinase inhibitors, these kinases can also antagonize one another. Consequently, the outcome of selective PLK1, aurora kinase A or aurora kinase B inhibition, compared with combined inhibition, will certainly be different.

  • Several treatment approaches have been proposed, which consist of PLK1, aurora kinase A or aurora kinase B inhibition combined with conventional chemotherapeutic agents that might enhance the efficacy and specificity of these drugs.

Abstract

Large numbers of inhibitors for polo-like kinases and aurora kinases are currently being evaluated as anticancer drugs. Interest in these drugs is fuelled by the idea that these kinases have unique functions in mitosis. Within the polo-like kinase family, the emphasis for targeted therapies has been on polo-like kinase 1 (PLK1), and in the aurora kinase family drugs have been developed to specifically target aurora kinase A (AURKA; also known as STK6) and/or aurora kinase B (AURKB; also known as STK12). Information on the selectivity of these compounds in vivo is limited, but it is likely that off-target effects within the same kinase families will affect efficacy and toxicity profiles. In addition, it is becoming clear that interplay between polo-like kinases and aurora kinases is much more extensive than initially anticipated, and that both kinase families are important factors in the response to classical chemotherapeutics that damage the genome or the mitotic spindle. In this Review we discuss the implications of these novel insights on the clinical applicability of polo-like kinase and aurora kinase inhibitors.

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Figure 1: Localization of PLK1, aurora kinase A and aurora kinase B in the dividing cell.
Figure 2: Cellular phenotypes induced by polo-like kinase and aurora kinase inhibitors.
Figure 3: Crosstalk between PLK1 and aurora kinase A in mitotic entry.
Figure 4: Crosstalk between PLK1 and aurora kinase B in the regulation of kinetochore–microtubule interactions.

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Acknowledgements

S.M.A.L. was supported by the Netherlands Organization for Scientific Research (NWO-Vidi: ZonMW 917.66.332) and the Dutch Cancer Society (UU2009-4311). R.H.M. was supported by the Netherlands Organization for Scientific Research (NWO-Vici: ZonMW 918.46.616, NWO-ALW 81802003, the Netherlands Genomics Initiative of NWO) and the Dutch Cancer Society (UU2006-3579).

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Authors and Affiliations

  1. Department of Medical Oncology and Cancer Genomics Centre, UMC Utrecht, Universiteitsweg 100, Stratenum 2. 118, Utrecht, 3584 CG, The Netherlands

    Susanne M. A. Lens, Emile E. Voest & René H. Medema

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  1. Susanne M. A. Lens
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  2. Emile E. Voest
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  3. René H. Medema
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Correspondence to Susanne M. A. Lens or René H. Medema.

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DATABASES

National Cancer Institute Drug Dictionary 

AZD1152

cisplatin

doxorubicin

ENMD-2076

LY2181308

MLN8054

MLN8237

paclitaxel

YM155

FURTHER INFORMATION

René H. Medema's homepage

Glossary

Taxanes

A group of chemotherapeutic agents (such as paclitaxel and its semi-synthetic analogue docetaxel) that stabilize microtubules and are considered to function as anti-mitotic drugs.

Vinca alkaloids

A class of chemotherapeutic agents (including, vincristine, vinblastine, vinorelbine, vindesine and vinflunine) originally isolated from periwinkle leaves (sometimes known as Vinca rosea) that destabilize microtubules and are considered to act as anti-mitotic drugs.

Anti-mitotic

A drug that induces a mitotic delay and subsequent cell death in mitosis.

Kinesins

A family of motor proteins that move along microtubules powered by the hydrolysis of ATP.

Central spindle

A bundled array of anti-parallel microtubules that forms between the segregating chromosomes in anaphase. It controls the position and assembly of the actinomyosin-based contractile ring required for cleavage furrow ingression and that regulates the final step of cytokinesis: abscission.

Midbody

A dense structure containing the central spindle and associated proteins that control cytokinesis. It connects the two newly formed daughter cells from telophase until final abscission.

Chromosomal passenger protein

A protein that localizes to the centromeric region of the chromosomes in prometaphase, moves from the chromosomes to the central spindle in anaphase and accumulates in the midbody in telophase.

Chemical genetics

A strategy whereby a kinase is genetically engineered to render it sensitive to synthetic ATP analogues.

Neutropenia

A haematological disorder characterized by an abnormally low number of neutrophils.

Mitotic checkpoint

A surveillance mechanism active in the mitotic cell that senses the attachment status of kinetochores and prevents anaphase onset until all kinetochores are stably connected to the mitotic spindle.

γ-tubulin ring complex

A large protein complex containing a ring of γ-tubulin subunits that can serve as a template for microtubule nucleation.

Cohesin

A complex of four subunits, structural maintenance of chromosomes 1 (SMC1), SMC3, SCC1 (also known as RAD21) and SCC3 (also known as STAG1 and STAG2 in vertebrates) that holds sister chromatids together after S phase and until anaphase.

Chrmosome disjunction

Severing of the cohesin linkage between paired sister chromatids.

KMN network

A conserved outer-kinetochore protein network consisting of KNL1 and the MIS12 and NDC80 protein complexes, a key player in kinetochore–microtubule attachments.

Central spindlin

A tetrameric complex consisting of a dimer of the kinesin 6 protein MKLP1 and a dimer of the Rho family GTPase-activating protein (GAP) CYK4 that localizes to the centre of the central spindle.

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Lens, S., Voest, E. & Medema, R. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 10, 825–841 (2010). https://doi.org/10.1038/nrc2964

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