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  • Review Article
  • Published:

Mining the Wnt pathway for cancer therapeutics

Nature Reviews Drug Discovery volume 5, pages 997–1014 (2006)Cite this article

A Corrigendum to this article was published on 01 March 2007

Key Points

  • Aberrant activation of the Wnt pathway is implicated in driving the formation of various human cancers, particularly those of the digestive tract.

  • Blocking this aberrant Wnt pathway activity in cancer cell lines efficiently inhibits their growth. Drugs designed to achieve this in the clinic are therefore predicted to be effective cancer therapeutics.

  • Long-term use of conventional non-steroidal anti-inflammatory drugs (NSAIDS) including aspirin might reduce the risk of developing some forms of cancers, including those driven by aberrant Wnt signalling activity. Studies using cancer cell lines and mouse models of colon cancer indicate that these NSAIDS might partially block cancer cell growth by reducing aberrant Wnt signalling activity.

  • Vitamins A and D derivatives are thought to have anticancer properties. This might be partly attributed to reduction of aberrant Wnt signalling in cancer cells through poorly defined mechanisms that include activation of nuclear receptors capable of reducing Tcf–β-catenin complex formation.

  • Preliminary studies indicate that antibodies specific for Wnt pathway components such as Wnt ligands or Frizzled receptors may effectively inhibit aberrant Wnt signalling in some Wnt-addicted cancers.

  • Preliminary results indicate that viral-based strategies targeting cancers with constitutive Wnt signalling have potential as effective cancer therapies. Strategies include generating oncolytic viruses that selectively replicate and kill cancer cells with high levels of Wnt signalling, and designing viruses that selectively express cytotoxic genes in these cancer cells.

  • High-throughput screening and structure-based design programs have identified small-molecule compounds capable of inhibiting aberrant Wnt signalling activity in cancer cells by blocking the formation of key protein complexes such as Tcf–β-catenin. Future challenges will be to improve on the selectivity and in vivo efficacy of these small-molecule inhibitors.

  • Identification of the Tcf–β-catenin target gene program inappropriately activated in Wnt-driven cancers should facilitate selection of novel targets for therapeutic antibodies or small-molecule inhibitors.

Abstract

Aberrant activation of the Wnt pathway is implicated in driving the formation of various human cancers, particularly those of the digestive tract. Inhibition of aberrant Wnt pathway activity in cancer cell lines efficiently blocks their growth, highlighting the great potential of therapeutics designed to achieve this in cancer patients. Here we provide an overview of the promise and pitfalls of current drug development strategies striving to inhibit the Wnt pathway and present new opportunities for therapeutic intervention.

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Figure 1: An overview of the Wnt signalling pathway.
Figure 2: Routes to aberrant activation of Wnt signalling in cancer cells.
Figure 3: Accumulation of β-catenin in adenomas.
Figure 4: A cell-based assay for screening compound libraries for small-molecule inhibitors of the Wnt pathway.
Figure 5: Secondary assays for evaluating potential Wnt inhibitors identified in primary high-throughput screens.

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Acknowledgements

We would like to thank J. van Es for critical reading of the manuscript and M. van den Born for providing the figure of β-catenin expression in adenoma tissues.

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  1. Hubrecht laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, Utrecht, 3584CT, The Netherlands

    Nick Barker & Hans Clevers

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FURTHER INFORMATION

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Glossary

Adenoma

An ordinarily benign neoplasm of epithelial tissue in which the tumour cells form glands or gland-like structures.

Carcinoma

The final, invasive stage of evolution of an epithelial cancer.

APCmin mouse

The APCmin (multiple intestinal neoplasia) mouse model of human familial adenomatous polyposis carries a germline mutation in the APC gene that drives the formation of multiple intestinal tumours.

Epigenetic

Any heritable influence (in the progeny of cells or of individuals) on chromosome or gene function that is not accompanied by a change in DNA sequence.

Apoptosis

Programmed cell death.

Isothermal titration μ-calorimetry

Thermodynamic technique for characterizing biomolecular interactions. This measures the heat absorbed or generated when two substances bind, enabling accurate determination of binding affinities and stoichiometries.

Familial adenomatous polyposis

Genetic disorder that is characterized by an increased predisposition to colorectal cancer, associated with germ-line mutations of the APC gene.

Oncolytic virus

Viruses engineered to selectively replicate in and kill cancer cells.

Prodrug

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism. It is generally designed to overcome problems associated with stability, toxicity, lack of specificity or limited (oral) bioavailability.

Antisense

DNA or RNA that is manipulated to be complementary to a target mRNA. Antisense techniques are used to inhibit the expression of genes in a sequence-specific fashion.

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Barker, N., Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5, 997–1014 (2006). https://doi.org/10.1038/nrd2154

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