Review
Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics

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Defects in p53 function, which occur frequently in human cancers due to mutations in TP53 or disruptions in the p53 regulatory pathway, render cells dependent on CHK1 (Checkpoint Kinase 1) to activate cell cycle checkpoints. In the presence of DNA damage or replication stress, inhibition of CHK1 leads to “mitotic catastrophe” and cell death in p53-deficient tumors while sparing p53-proficient cells. CHK1 inhibitors sensitize tumors to a variety of DNA-damaging agents or antimetabolites in preclinical models and are being evaluated in early phase clinical trials. In this review, we summarize recent advances and controversies in the development and application of CHK1 inhibitors as cancer therapeutics.

Section snippets

Synthetic lethal strategy for killing p53-deficient cancers: the concept and its evolution

In 1982, Lau and Pardee reported that caffeine treatment forced BHK (Baby Hamster Kidney) cells arrested in G2 (Gap 2) of the cell cycle with nitrogen mustard (HN2) to enter into a premature, lethal mitosis. The authors concluded that caffeine potentiated the lethality of HN2 by forcing cells with damaged DNA to undergo mitosis before properly repairing the DNA lesions [1]. Subsequent studies have demonstrated that caffeine could also drive S (Synthesis)-phase arrested cells into a lethal

The CHK1 pathway

ATM, ATR and CHK1 are key components of cell cycle checkpoints (Figure 2 and Box 1) that become engaged when cells experience replication stress (ATR/CHK1) or when DNA double-strand breaks are generated (ATM/ATR/CHK1) [15]. CHK1 is phosphorylated by ATR under these conditions and signals to the cell cycle machinery to arrest cells in the S- and G2-phases of the cell division cycle. The cell division cycle (CDC)25A protein phosphatase is a key downstream effector of CHK1 14, 16. CHK1 negatively

Deregulation of CHK1 in human cancers

Hereditary CHK1 mutations have not been identified in cancer predisposition syndromes [21]. This is in contrast to several other checkpoint-pathway components such as TP53, CHK2, BRCA1 and ATM, where mutation gives rise to familial cancer syndromes. However, low levels of CHK1 expression and deletions of the distal end of chromosome 11q, including 11q24 containing the CHK1 locus, frequently accompany amplification of the Cyclin D1 locus at 11q13 and contribute to tamoxifen resistance in

Clinical translation of CHK1 inhibitors

UCN-01, a nonselective CHK1 inhibitor, has been tested in phase I trials in patients with cancer either as a single agent or in combination with a variety of chemotherapy agents including irinotecan 36, 37, topotecan 38, 39, cisplatin 40, 41, carboplatin [42], 5-fluorouracil [43] or cytarabine [44]. Results indicate UCN-01 has disappointing pharmacokinetic profiles and has produced limited antitumor outcomes. In contrast to predictions from the preclinical pharmacokinetic data, UCN-01 had a

Newer generation selective CHK1 inhibitors

Unfavorable pharmacokinetics and untoward toxicities have hindered further clinical development of UCN-01. In addition to CHK1, UCN-01 is also a potent inhibitor of several additional protein kinases including PKC (Protein kinase C), PDK1, CDK1 and CDK2. In the past several years, many next generation ATP-competitive inhibitors (Table 1) with improved selectivity for CHK1, such as AZD7762, PF477736 and SCH900776, have been developed. These newer inhibitors are showing promise in preclinical

CHK1 inhibitors in combination with IR as a therapeutic strategy

CHK1 inhibitors and CHK1 knockdown enhance the cytotoxicity of IR in various cancer cell lines in vitro and xenograft models in vivo 9, 49, 50, 56, 57. Morgan et al. monitored the ability of the selective CHK1 inhibitor AZD7762 to further enhance the gemcitabine-mediated radiosensitization in pancreatic cell lines and xenografts [50]. Despite the positive results reported in these studies, CHK1 inhibitors have not been tested as radiosensitizers in cancer patients. As discussed above, the

CHK1 or CHK2?

The CHK1 inhibitors described above all potently inhibit CHK1 but have varying degrees of activity against CHK2. Although AZD7762 is equipotent against CHK2, PF477736 is 100-fold more selective for CHK1, and SCH900776 is 500-fold more selective for CHK1 than CHK2. Clinically effective doses of either AZD7762 or PF477736 are likely to potently inhibit both CHK1 and CHK2. By contrast, drug levels of SCH900776 required for PD activity targeting CHK1 are not expected to reach levels that would

Concluding remarks

A new generation of more selective CHK1 inhibitors are currently undergoing clinical evaluation in combination with agents that either induce DNA damage (i.e. Topoisomerase I inhibitors) or interfere with DNA replication (antimetabolites) with the goal of enhancing the cytotoxicity of these agents. Although originally developed to selectively target p53-deficient tumors, CHK1 inhibitors might be equally effective in killing tumors with an intact p53 pathway. Activating the S-phase checkpoint

Disclosures

J.W.J. is a former employee of AstraZeneca.

Glossary

  • Base excision repair: a type of DNA repair whereby an altered base is removed by a DNA glycosylase enzyme, followed by excision of the resulting sugar phosphate. The small gap left in the DNA helix is filled in by the sequential action of DNA polymerase and DNA ligase.

  • Cmax: a pharmacokinetic term describing the peak blood plasma concentration of a drug.

  • Clearance: a pharmacokinetic term representing the volume of plasma cleared of the drug per

Acknowledgements

A grant from the Komen Foundation to H.P.-W. and C.X.M. supports preclinical CHK1 inhibitor studies. H.P.-W. is an Investigator of the Howard Hughes Medical Institute.

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