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Kinesins and cancer

Nature Reviews Cancer volume 12, pages 527–539 (2012)Cite this article

Subjects

Key Points

  • More than 650 members of the kinesin superfamily have been discovered in eukaryotic organisms. They are categorized into 14 subfamilies on the basis of sequence homology and classified as mitotic kinesins, which are involved in cell division, and non-mitotic kinesins, which are principally involved in intracellular transport.

  • The mitotic spindle is a validated target in cancer chemotherapy, and several agents that target tubulin and that interfere with microtubule dynamics are in clinical use. This success has triggered the search for additional mitotic spindle targets, including mitotic kinases (such as cyclin-dependent kinases, Aurora kinase A, Aurora kinase B and Polo-like kinase 1) and specific mitotic kinesins.

  • EG5 and centromere-associated protein E (CENPE) are two mitotic kinesins that have received much of this attention. Specific inhibitors have been developed and are currently in multiple Phase I or Phase II clinical trials. Other kinesins are also considered potential therapeutic targets and candidate inhibitors have been described.

  • Several non-mitotic kinesins are also involved in tumorigenesis and in the development of resistance to anticancer agents.

  • Several kinesins have multiple functions in mitosis or in intracellular transport. Therefore, careful validation is needed to identify any important side effects and to clarify whether they are viable cancer drug targets.

Abstract

Kinesins are a family of molecular motors that travel unidirectionally along microtubule tracks to fulfil their many roles in intracellular transport or cell division. Over the past few years kinesins that are involved in mitosis have emerged as potential targets for cancer drug development. Several compounds that inhibit two mitotic kinesins (EG5 (also known as KIF11) and centromere-associated protein E (CENPE)) have entered Phase I and II clinical trials either as monotherapies or in combination with other drugs. Additional mitotic kinesins are currently being validated as drug targets, raising the possibility that the range of kinesin-based drug targets may expand in the future.

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Figure 1: Functions of human kinesins at different stages of mitosis and cytokinesis.
Figure 2: Simplified model of the roles of different mitotic kinesins during mitosis in a kinesin-centric view.
Figure 3: Kinesin inhibitors in clinical development.

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Acknowledgements

The authors would like to thank Cancer Research UK for financial support. They regret that they were unable to include the work of many groups who have contributed to the understanding of the functions of various kinesins from non-human species.

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  1. The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Bearsden, Scotland, UK

    Oliver Rath & Frank Kozielski

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Correspondence to Frank Kozielski.

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Supplementary information

Supplementary information S1

Human kinesin nomenclature and function (PDF 451 kb)

Supplementary information S2

Published work describing kinesin-targeting inhibitors in clinical development (PDF 353 kb)

Supplementary information S3

Human mitotic kinesins and their motor classification. (PDF 393 kb)

Glossary

Monoastral spindle phenotype

An array of microtubules surrounded by a ring of chromosomes.

Merotelic kinetochore attachment

A single kinetochore becomes attached to microtubules from both spindle poles.

Optical tweezers

An instrument that uses a highly focused laser beam to manipulate microscopic objects (for example, biopolymers such as microtubules or molecular motors) and to measure forces.

Endoreduplication

Replication of the genome in the absence of cell division resulting in polyploidy.

Hypereosinophilia

A haematopoietic disease characterized by an unusually high eosinophil count.

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Rath, O., Kozielski, F. Kinesins and cancer. Nat Rev Cancer 12, 527–539 (2012). https://doi.org/10.1038/nrc3310

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