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Drug Insight: small-molecule inhibitors of protein kinases in the treatment of thyroid cancer

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 42–52 (2006)Cite this article

Abstract

Molecular targeting of protein kinases is a new paradigm in the treatment of cancer. The clinical efficacy of low-molecular weight inhibitors of ABL, stem-cell growth-factor receptor, and the epidermal growth factor receptor in different tumor types is witness to the power of this approach. The presence of activating mutations of a kinase, or an increased gene copy number, might anticipate tumor responsiveness to its targeting. Thyroid cancer is the most prevalent endocrine malignancy and is frequently associated with the oncogenic conversion of two specific protein kinases, RET and BRAF. Small-molecule inhibitors of both kinases have already reached the clinical testing stage. Protein kinases other than RET and BRAF are also being evaluated for their potential in thyroid-cancer treatment.

Key Points

  • Thyroid cancer is the most prevalent endocrine malignancy

  • It is frequently associated with the activation of specific protein kinases

  • There is good evidence that alterations in at least two kinases, RET and BRAF, are causative events in thyroid-cancer initiation

  • Molecular targeting of RET and BRAF holds promise for thyroid-cancer treatment

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Figure 1: Schematic drawing of the RET protein with the four extracellular cadherin-like domains, the cysteine-rich box adjacent to the plasma membrane, the intracellular juxtamembrane domain and the split tyrosine kinase domain.
Figure 2: Structure of the BRAF protein, denoting the three conserved regions: conserved region 1 contains the RAS-binding domain and conserved region 3 is the kinase domain.

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Acknowledgements

We thank members of our laboratory for their comments and advice and Jean A Gilder for text editing. We apologize to the many colleagues whose work we have not cited because of space limits.

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Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, via S Pansini 5, Naples, 80131, Italy

    Massimo Santoro

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Correspondence to Massimo Santoro.

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The authors declare that their research has been partly supported by grants from AstraZeneca (Alderley Park, Macclesfield, Cheshire, UK) and Bayer HealthCare Pharmaceuticals (West Haven, Connecticut, USA).

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Santoro, M., Carlomagno, F. Drug Insight: small-molecule inhibitors of protein kinases in the treatment of thyroid cancer. Nat Rev Endocrinol 2, 42–52 (2006). https://doi.org/10.1038/ncpendmet0073

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