Role of BRAF in Thyroid Oncogenesis
Cet article passe en revue le rôle des mutations du gène BRAF, notamment la mutation V600E, dans la genèse des carcinomes de la thyroïde
BRAF, a cytoplasmic serine/threonine protein kinase, plays a critical role in cell signaling as an activator within the MAPK pathway. The most common BRAF mutation is the V600E transversion, which causes constitutive kinase activity. This mutation has been found in a multitude of human cancers, including both papillary (PTC) and papillary derived-anaplastic thyroid carcinoma (ATC), where it initiates follicular cell transformation. With such a high frequency of BRAF mutations in PTC (44%) and PTC-derived ATC (24%), research in BRAFV600E detection for diagnostic purposes for has shown high sensitivity and specificity for tumor cell presence. BRAFV600E in PTC has also provided valuable prognostic information, as its presence has been correlated with more aggressive and iodine-resistant phenotypes. Such findings have initiated research in targeting oncogenic BRAF in cancer therapeutics. Although multiple phase II clinical trials in patients with iodine refractory metastatic PTC have demonstrated significant efficacy for sorafenib, a first generation BRAF inhibitor, the mechanism by which it mediates its effect remains unclear due to multiple additional kinase targets of sorafenib. Additionally, pre-clinical and clinical studies investigating combination therapy with agents such as selective (PLX 4032) and potent (BAY 73-4506 and ARQ 736) small molecule BRAF inhibitors and MAP/ERK kinase inhibitors (AZD6244) hold great promise in the treatment of BRAFV600E cancers and may eventually play a powerful role in changing clinical course of PTC and ATC.