Is BRAF the Achilles' Heel of thyroid cancer?

In this issue of Clinical Cancer Research , Ouyang et al. (1) present evidence suggesting that BRAF is a therapeutic target in thyroid cancer. Previous studies have shown that BRAF is mutated in a high proportion of thyroid cancers, but the therapeutic implications of this have not been investigated. In this article, Ouyang et al. show that small-molecule inhibitors of BRAF can block the growth of thyroid cancer cells expressing mutant BRAF, suggesting that new strategies could be developed to exploit the high rate of mutations in this protein kinase in thyroid cancer. Thyroid cancer accounts for f1% of all new cases of cancer each year (f0.5% in men and 1.5% in women). There are f26,000 new cases of thyroid cancer in America each year with f2,400 deaths and in Europe there are f16,000 new cases, with f3,200 deaths. Thus, thyroid cancer is a relatively rare disease, but it is the most common malignancy of endocrine tissues and, importantly, in the United States its annual incidence has increased by f50% in the last 25 years (2). Thyroid cancer is divided into four distinct classes: follicular epithelial cell–derived papillary thyroid cancer, which accounts for 80% of cases; follicular thyroid cancer (15% of cases); anaplastic thyroid cancer (2% of cases); and parafollicular C cell–derived medullary thyroid cancer (3% of cases; ref. 3). Thyroid cancer is not particularly life threatening. Papillary thyroid cancer patients are treated with thyroidectomy and then radioiodine (I) is administered to remove residual thyroid tissue and treat metastatic disease. [I]radioiodine is safe and effective because thyroid tissues preferentially absorb iodine. Finally, the patients receive lifelong thyroxine to suppress production of thyroid-stimulating hormone, which stimulates proliferation of thyroid tissues. Consequently, the majority of papillary thyroid cancer patients can be cured and can expect an average 40-year relative survival rate of 84% (4). Most follicular thyroid cancer patients can also be cured, with an average 40-year survival rate of f94% (4). Some papillary thyroid cancer patients cannot be cured, however, either because their tumors are inoperable or fail to absorb radioiodine. In addition, in rare cases, papillary thyroid cancer progresses from well differentiated to poorly differentiated or undifferentiated carcinomas and this leads to significantly reduced survival rates. It is also difficult to treat anaplastic thyroid cancer and medullary thyroid cancer, therefore these patients also have significantly reduced survival rates. It is important then to develop novel treatment strategies for patients with incurable thyroid cancer and, to this end, it is important to improve diagnosis, which largely relies on histopathology data and clinicopathologic criteria. These are often incomplete until surgery has been done. To improve both diagnosis and treatment, therefore, it is important to understand the molecular mechanisms that underlie thyroid cancer initiation and progression and to determine how different mutations affect the distinct subtypes of disease. Recent advances have gone some way to achieving this. The cell signaling pathways that lie downstream of the classic receptor tyrosine kinases have been implicated in human cancer for many years. These pathways normally regulate cellular responses to changing environmental conditions. They are activated when peptide growth factors interact with receptor tyrosine kinases in the cell membrane, bringing about a series of events that lead to activation of several intracellular signaling pathways (5). One such pathway that has been much studied is the RAS-RAF-mitogen-activated kinase/extracellular signalregulated kinase (ERK) kinase (MEK)-ERK pathway (Fig. 1; ref. 6), which regulates cell proliferation, survival, and differentiation. RAS is a small G protein that is embedded in the inner leaflet of the plasma membrane and, once activated, it recruits the protein kinase RAF to the plasma membrane. RAF is activated at the plasma membrane and it then activates the protein kinase MEK, which, in turn, activates the protein kinase ERK (6). ERK phosphorylates several proteins to regulate gene expression, cytoskeletal rearrangements, and metabolism. The RAS-RAF-MEK-ERK pathway is hyperactivated in f30% of human cancers (7), where it provides growth and survival signals. Growth factors can be overexpressed and receptor tyrosine kinases mutated or amplified, thereby stimulating constitutive receptor tyrosine kinase signaling. Similarly, activating mutations in RAS occur in f15% of human cancers (8). Finally, BRAF , one of the three RAF genes in humans (along with ARAF and CRAF) is mutated in f7% of human cancers (9, 10). ARAF and CRAF are not commonly mutated in cancer because their regulation is fundamentally different from that of BRAF and therefore they are not predisposed to activating mutations (11). This signaling pathway also plays an important role in thyroid cancer. The receptor tyrosine kinase RET is not normally expressed in thyroid follicular cells. RET gene