Thyroid carcinoma: molecular pathways and therapeutic targets.

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.