Thyroid carcinoma: molecular pathways and therapeutic targets

Abstract

Thyroid cancer is the most common malignant tumor of the endocrine system. The most frequent type of thyroid malignancy is papillary carcinoma. These tumors frequently have genetic alterations leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Most common mutations in papillary carcinomas are point mutations of the BRAF and RAS genes and RET/PTC rearrangement. These genetic alterations are found in >70% of papillary carcinomas and they rarely overlap in the same tumor. Most frequent alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPARgamma rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. A number of compounds have been studied and showed antitumor effects in preclinical studies and are being tested in ongoing clinical trials.

Fig. 1

The mitogen-activated protein kinase (MAPK) signaling pathway is physiologically activated by binding of growth factors to receptor tyrosine kinases (RTKs), such RET and NTRK, resulting in receptor dimerization and activation via autophosphorylation of tyrosine residues in the intracellular domain. The activated receptor, through a series of adaptor proteins, leads to activation of RAS located at the inner face of the plasma membrane. The activated RAS binds to and recruits RAF proteins (mainly BRAF in thyroid follicular cells) to the plasma membrane. Activated BRAF phosphorylates and activate the mitogen-activated protein kinase/ERK kinase (MEK), which in turn phosphorylates and activates the extracellular-signal-regulated kinase (ERK). Activated ERK translocates into the nucleus, where it regulates transcription of the genes involved in cell differentiation, proliferation and survival. Alterations of this pathway in thyroid cancer can occur at different levels as a result of point mutation or rearrangement involving the RET, RAS, and BRAF genes.