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  • Review Article
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Targeting the checkpoint kinases: chemosensitization versus chemoprotection

Nature Reviews Cancer volume 4, pages 216–225 (2004)Cite this article

Key Points

  • DNA-damaging agents are among the most effective anticancer agents in clinical use; however, they have significant limitations. Many patients with cancer either do not respond, or develop resistance to them, they are also toxic, and have only a limited therapeutic window.

  • The DNA-damage-response network regulates not only cell-cycle checkpoints, but also DNA repair, genome maintenance, senescence and apoptosis. Modulation of the DNA-damage response, depending on where in the network this modulation occurs, could have different consequences including chemosensitization and chemoprotection.

  • CHK1 and CHK2 were originally discovered as checkpoint kinases. However, further studies have indicated that they are actually DNA-damage-response kinases, regulating more than just cell-cycle checkpoints.

  • CHK1 regulates numerous checkpoint pathways, including S-phase and G2–M checkpoints. Other potential CHK1 functions include replication, chromatin remodelling and DNA repair. CHK1 inhibition is expected to sensitize cells to a broad spectrum of DNA-damaging agents.

  • CHK2 might have a redundant and supportive role in checkpoints, but its role in ionizing-radiation-induced apoptosis is more prominent. However, its role in other DNA-damage-induced apoptosis mechanisms is less well established. CHK2 inhibition is expected to protect normal cells from the side effects of ionizing radiation, but its role in chemoprotection still needs to be clarified.

Abstract

An important part of the cellular response to DNA damage is checkpoint activation — checkpoint kinases CHK1 and CHK2 phosphorylate key proteins to elicit cell-cycle blocks. Inhibiting these kinases was believed to sensitize tumour cells to cancer treatments that damage DNA, because in the absence of checkpoints and efficient DNA repair, the response would switch to cell death or senescence. Recent discoveries have, however, highlighted different and expanded roles for CHK1 and CHK2, so should the therapeutic hypothesis that is concerned with targeting so-called checkpoint kinases be modified?

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Figure 1: Functions and regulations of CHK1 in the mammalian DNA-damage-response network.
Figure 2: Functions and regulations of CHK2 in the mammalian DNA-damage-response network.

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Acknowledgements

B.Z. would like to acknowledge helpful discussions with S. Davis and E. Rowinsky during the course of writing this review.

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Authors and Affiliations

  1. Drug Discovery Biology, Incyte Corporation, Experimental Station, Rt. 141 & Henry Clay Road, Bldg 400, Wilmington, 19880, DE, USA

    Bin-Bing S. Zhou

  2. Department of Cell Cycle and Cancer, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark

    Jiri Bartek

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  1. Bin-Bing S. Zhou
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Correspondence to Bin-Bing S. Zhou.

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ABL

AKT

ATM

ATR

BAX

BCR

BRCA1

CDC25A

CDC25C

CHK1

CHK2

claspin

E2F1

p53

PML

SMC1

Glossary

THERAPEUTIC WINDOW

The ratio between the toxic dose and the therapeutic dose of a drug, used as a measure of the relative safety of the drug for a particular treatment. Also called therapeutic index.

ATAXIA TELANGIECTASIA

(AT). AT belongs to a group of human diseases collectively known as 'genomic instability syndromes'. It is characterized by cerebellar degeneration — which leads to severe, progressive neuromotor dysfunction — immunodeficiency, genomic instability, thymic and gonadal atrophy, and a striking predisposition to lymphoreticular malignancies. It is associated with defects in the ATM gene, a member of the phosphatidylinositol 3-kinase superfamily.

CELL-CYCLE CHECKPOINTS

Regulatory mechanisms that do not allow the initiation of a new phase of the cell cycle before the previous one is completed, or temporarily arrest cell-cycle progression in response to stress. DNA damage activates specific checkpoints at the G1–S and G2–M boundaries, and in S phase, with each one based on a different mechanism.

MITOTIC CATASTROPHE

A series of cellular events that occur after premature and aberrant mitosis and that usually result in cell death. Such a mitosis does not produce proper chromosome segregation and cell division, but leads to the formation of large non-viable cells with several nuclei, which contain fractions of broken chromosomes.

RADIORESISTANT DNA SYNTHESIS

Characteristic inability to arrest DNA synthesis after irradiation, commonly seen in cells from patients with ataxia telangiectasia and those who are defective in other components of the intra-S-phase checkpoint.

XEROSTOMIA

Dryness of the mouth resulting from diminished or arrested salivary secretion

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Zhou, BB., Bartek, J. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4, 216–225 (2004). https://doi.org/10.1038/nrc1296

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