Targeting BRAF in thyroid cancer

Abstract

Activating mutations in the gene encoding BRAF are the most commonly identified oncogenic abnormalities in papillary thyroid cancer. In vitro and in vivo models have demonstrated that overexpression of activated BRAF induces malignant transformation and aggressive tumour behaviour. BRAF and other RAF kinases are frequently activated by other thyroid oncogenes and are important mediators of their biological effects including dedifferentiation and proliferation. Because current therapeutic options for patients with thyroid cancers that are aggressive and/or do not respond to standard therapies are limited, BRAF and its downstream effectors represent attractive therapeutic targets. In this review, data supporting a role for BRAF activation in thyroid cancer development and establishing the potential therapeutic efficacy of BRAF-targeted agents in patients with thyroid cancer will be reviewed.

Figure 1

Activation of the RAS–RAF–MEK pathway in thyroid cancer. Constitutive activation via gene mutations or rearrangements in RET, RAS and BRAF (highlighted in red) are the principal initiators of thyroid cancer development through enhanced nuclear translocation of ERK and subsequent transcriptional regulation of target genes. Activation of this tumour initiation pathway occurs in ∼70% of thyroid cancers. Activation of other pathways that cooperatively activate ERK, as well regulate other cell signaling pathways may also be involved with ERK in thyroid cancer progression. ^*Proteins known to be constitutively activated in thyroid cancer.