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Tankyrase-targeted therapeutics: expanding opportunities in the PARP family

Nature Reviews Drug Discovery volume 11, pages 923–936 (2012)Cite this article

Subjects

Key Points

  • The tankyrases TANK1 and TANK2 are members of the poly(ADP-ribose) polymerase (PARP) superfamily of enzymes that catalyse the transfer of many ADP-ribose moieties onto their protein substrates. They have roles in telomere maintenance, WNT signalling, mitosis and insulin-mediated glucose uptake.

  • Another member of the PARP superfamily, PARP1, is involved in DNA damage signalling and base excision repair. It has been the focus of many drug development efforts, particularly for the treatment of cancers with mutations in breast cancer susceptibility type 1 (BRCA1) or BRCA2, as simultaneous inhibition of the base excision and homologous repair pathways has a synthetic lethal effect on cancer cells; however, so far, no PARP1 inhibitors have been approved for clinical use.

  • The WNT pathway controls cellular proliferation and differentiation through the transcriptional activity of β-catenin, which is degraded by a complex including the tankyrase substrate axis inhibition protein (AXIN) when WNT signalling is not active. This pathway is dysregulated in many cancers, leading to constitutive β-catenin activity, but contains few 'druggable' targets.

  • The role of tankyrases in WNT signalling has driven the development of tankyrase-specific PARP inhibitors, which have now been shown to reduce β-catenin transcriptional activity in cancer cells and effectively kill cells with mutations in the β-catenin destruction complex component adenomatous polyposis coli (APC).

  • This exciting new class of PARP inhibitors could be useful in treating cancer as well as other conditions such as pulmonary fibrosis; however, lessons must be learned from the clinical development of PARP1 inhibitors. Careful preclinical work and clinical trial design is essential for the success of tankyrase inhibitors in the clinic.

Abstract

The poly(ADP-ribose) polymerase (PARP) protein superfamily has wide-ranging roles in cellular processes such as DNA repair and WNT signalling. Efforts to pharmacologically target PARP enzymes have largely focused on PARP1 and the closely related PARP2, but recent work highlighting the role of another family member, tankyrase 1 (TANK1; also known as PARP5A and ARTD5), in the control of WNT signalling has fuelled interest in the development of additional inhibitors to target this enzyme class. Tankyrase function is also implicated in other processes such as the regulation of telomere length, lung fibrogenesis and myelination, suggesting that tankyrase inhibitors could have broad clinical utility. Here, we discuss the biology of tankyrases and the discovery of tankyrase-specific inhibitors. We also consider the challenges that lie ahead for the clinical development of PARP family inhibitors in general.

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Figure 1: PARsylation by PARPs.
Figure 2: Tankyrase structure.
Figure 3: Tankyrase functions.

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Acknowledgements

Work in our laboratory is funded by the UK Wellcome Trust as part of the Seeding Drug Discovery Initiative, Breakthrough Breast Cancer, Cancer Research UK, American Association for Cancer Research, Breast Cancer Research Foundation, the Breast Cancer Campaign and Susan G. Komen for the Cure Foundation. We acknowledge National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Royal Marsden Hospital Biomedical Research Centre.

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Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Jenna L. Riffell, Christopher J. Lord & Alan Ashworth

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  1. Jenna L. Riffell
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  2. Christopher J. Lord
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  3. Alan Ashworth
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Correspondence to Christopher J. Lord or Alan Ashworth.

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Competing interests

C.J.L. and A.A. are inventors on patents describing the use of poly(ADP-ribose) polymerase (PARP) inhibitors and stand to gain under the ICR Rewards to Inventors Scheme.

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FURTHER INFORMATION

UK Institute of Cancer Research

Pfam database

Protein Data Bank

Glossary

iTRAQ

Isobaric tag for relative and absolute quantification; a proteomic technique that quantifies isotope-tagged proteins from different samples in one experiment.

Sister chromatid cohesion

The state in which two sister chromatids are bound together by the cohesin complex during mitosis, from prophase to metaphase.

Cherubism

A genetic disorder that results in bone, fibrous tissue and cyst formations along the jawline and lower part of the face. This disorder was originally termed cherubism owing to a perceived resemblance of sufferers to cherubs in Renaissance paintings.

Synthetic lethality

A relationship between the functions of two gene products; defined as a situation whereby a mutation or loss of function in either gene alone is compatible with viability, but defects in both genes lead to cell death.

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Riffell, J., Lord, C. & Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discov 11, 923–936 (2012). https://doi.org/10.1038/nrd3868

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