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 470% 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-PPARc 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. Modern Pathology ( Keywords: thyroid cancer; mutations; MAPK; BRAF; RET; inhibitors Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases.1 The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes B80% of all cases. Papillary carcinomas frequently have genetic alterations leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway (Figure 1). Those include RET/ PTC rearrangement and point mutations of the BRAF and RAS genes. Mutations involving one of these genes are found in 470% of papillary carcinomas and they rarely overlap in the same tumor 2-4 (Table 1). Frequent genetic alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPARg 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. BRAFBRAF serine-threonine kinase belongs to the family of RAF proteins, which are intracellular effectors of the MAPK signaling cascade. Upon activation triggered by RAS binding and protein recruitment to the cell membrane, these kinases phosphorylate and activate MEK, which in turn activates ERK and consequent effectors of the MAPK cascade.Point mutations of the BRAF gene are found in B45% of thyroid papillary carcinomas.2,5 Virtually all point mutations involve nucleotide 1799 and result in a valine-to-glutamate substitution at residue 600 (V600E).6,7 BRAF V600E mutation leads to constitutive activation of BRAF kinase and the mechanism of activations has been recently elucidated. In the dephosphorylated, wild-type BRAF protein, the hydrophobic interactions between the activation loop and the ATP binding site maintain the protein in an inactive conformation. The V600E subs...

An update on molecular biology of thyroid cancers

“…As RAS binds and activates BRAF, it is translocated to the cell membrane and directly associates with the MAPK signaling pathway [14]. BRAF phosphorylates and activates MEK, which in turn activates ERK and all the downstream effector molecules of MAPK.…”

“…Activated ERK and ELK1 translocate to the nucleus and regulate transcription of genes involved in cell differentiation, proliferation, and survival ( Fig. 1) [26,14]. The most common genetic changes in PTC include point mutations of BRAF which are observed in 35-70% of papillary thyroid carcinomas [29,30].…”

“…More than 95% of BRAF mutations detected in thyroid cancers are thymine to adenine transversions at position 1799 (T1799A) resulting in the substitution of valine by glutamate at residue 600 (V600E) ( Table 1) [31]. This mutation causes constitutive activation of BRAF kinase and, thus, induction of the MAPK signaling pathway, which is responsible for thyroid tumorigenesis [14,31]. In small percentages of PTC, K601E point mutation, small deletions or insertion around codon 600 and AKAP9/BRAF rearrangement are also be observed [30].…”

“…PTCs frequently have genetic alterations such as point mutations of BRAF and RAS genes and RET/PTC rearrangements. These genetic alterations are found in more than 70% of the patients and may have prognostic implications [14][15][16][17].…”

“…Treatment strategy is thyroidectomy followed by ablative or metastatic doses of radioiodine therapy [12,13,18,19]. Approximately 50% of FTC patients have mutations in RAS family genes or PAX-PPAR␥ rearrangements [14,20,21].…”