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Journal of Thyroid Research
Volume 2011 (2011), Article ID 678357, 10 pages
http://dx.doi.org/10.4061/2011/678357
Review Article

How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer

1Cancer Biology Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal
2Molecular Pathology Service, Portuguese Institute of Oncology of Coimbra FG, EPE, Avenida Bissaya Barreto, 98, 3000-075 Coimbra, Portugal
3Department of Pathology, Faculty of Medicine of Porto University, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
4Endocrinology Service, Portuguese Institute of Oncology of Coimbra FG, EPE, Avenida Bissaya Barreto, 98, 3000-075 Coimbra, Portugal
5Abel Salazar Biomedical Sciences Institute (ICBAS), Lg. Prof. Abel Salazar, 4099-003 Porto, Portugal
6Department of Pathology, Hospital São João, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

Received 11 February 2011; Accepted 10 April 2011

Academic Editor: Maria João M. Bugalho

Copyright © 2011 Hugo Prazeres et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The significance of RET in thyroid cancer comes from solid evidence that, when inherited, an RET activating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. The RET gene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature of RET point mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs.