RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Abstract

Hereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of-function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, and will summarize the therapies designed to strategically interfere with the pathologic activation of the RET oncogene.

Figure 1. Structure of the RET tyrosine kinase receptor and strategies for targeting RET activation

The RET receptor tyrosine kinase consists of three functional domains: an extracellular domain with four cadherin-like repeats, a cysteine rich region, and an intracellular tyrosine kinase region. Various strategies for targeting RET activation include tyrosine kinase inhibitors, targeting downstream pathways, homodimerization inhibitors, expression inhibitors, and autophosphorylation inhibitors.