RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors

• Published in: Endocrine reviews Vol. 27; no. 5; pp. 535 - 560
• Main Authors: de Groot, Jan Willem B, Links, Thera P, Plukker, John T. M, Lips, Cornelis J. M, Hofstra, Robert M. W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.08.2006; Oxford University Press; Copyright by The Endocrine Society
• Subjects: Animals; Aptamers; Biological and medical sciences; Cancer; Cancer therapies; Cell differentiation; Cell migration; Cell proliferation; Cell survival; Disorders; Embryogenesis; Embryonic growth stage; Endocrine Gland Neoplasms - diagnosis; Endocrine Gland Neoplasms - genetics; Endocrine Gland Neoplasms - therapy; Fetal Development - genetics; Fundamental and applied biological sciences. Psychology; Gene Targeting; Gene therapy; Genetic screening; Genetic Therapy; Haplotypes; Humans; Kinases; Ligands; Models, Biological; Monoclonal antibodies; Multiple endocrine neoplasia; Multiple Endocrine Neoplasia Type 2a - diagnosis; Multiple Endocrine Neoplasia Type 2a - genetics; Multiple Endocrine Neoplasia Type 2a - therapy; Mutation; Neural crest; Nuclease; Papillary thyroid carcinoma; Point mutation; Polymorphism, Genetic; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins c-ret - antagonists & inhibitors; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - physiology; Receptors; Ret protein; Signal Transduction - drug effects; Therapeutic targets; Thyroid; Thyroid cancer; Thyroidectomy; Tyrosine; Vertebrates: endocrinology; Hereditary; Tumor; Review
• ISSN: 0163-769X; 1945-7189
• DOI: 10.1210/er.2006-0017

The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.