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Clin Cancer Res. 2011 Dec 15;17(24):7511-7. doi: 10.1158/1078-0432.CCR-11-1155. Epub 2011 Sep 7.

Role of BRAF in thyroid oncogenesis.

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  • 1Ohio State University College of Medicine, Divisions of Surgical Oncology and Medical Oncology, James Cancer Center & Solove Research Institute, Columbus, OH 43210, USA.

Abstract

BRAF, a cytoplasmic serine-threonine protein kinase, plays a critical role in cell signaling as an activator within the mitogen-activated protein kinase (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 thyroid cancer (PTC) and papillary-derived anaplastic thyroid cancer (ATC), in which it initiates follicular cell transformation. With such a high frequency of BRAF mutations in PTC (44%) and PTC-derived ATC (24%), research in BRAF(V600E) detection for diagnostic purposes has shown high sensitivity and specificity for tumor cell presence. BRAF(V600E) 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 shown significant efficacy for sorafenib, a first-generation BRAF inhibitor, the mechanism by which it mediates its effect remains unclear because of multiple additional kinase targets of sorafenib. Additionally, preclinical 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/extracellular signal-regulated kinase (ERK) kinase inhibitors (AZD6244) hold great promise in the treatment of BRAF(V600E) cancers and may eventually play a powerful role in changing the clinical course of PTC and ATC.

©2011 AACR.

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