BRAF belongs to a family of serine-threonine protein kinases that includes ARAF, BRAF, and CRAF (RAF1). RAF kinases are central mediators in the MAP kinase signaling cascade and exert their effect predominantly through phosphorylation and activation of MEK. This occurs following the dimerization (hetero- or homo-) of the RAF molecules. As part of the MAP kinase pathway, RAF is involved in many cellular processes, including cell proliferation, differentiation, and transcriptional regulation.
Mutant BRAF has been implicated in the pathogenesis of several cancers, including melanoma, non-small cell lung cancer, colorectal cancer, papillary thyroid cancer, and ovarian cancer (Davies et al. 2002).
Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: September 19, 2012
Approximately 8–15% of colorectal cancer (CRC) tumors harbor BRAF mutations (De Roock et al. 2009; Rizzo et al. 2010; Tejpar et al. 2010). The presence of BRAF mutation is significantly associated with right-sided colon cancers and is associated with decreased overall survival (Roth et al., 2010). Several studies have reported that patients with metastatic CRC (mCRC) that harbor BRAF mutations do not respond to anti-EGFR antibody agents cetuximab or panitumumab in the chemotherapy-refractory setting (Bardelli and Siena 2010; Folprecht et al. 2010; Gravalos et al. 2010; Lievre, Blons, and Laurent-Puig 2010). Based on these findings, BRAF mutations were suggested to be a negative predictor of response to anti-EGFR therapy (De Roock et al. 2009; Mao et al. 2011; Rizzo et al. 2010; Sharma and Gulley 2010; Tejpar et al. 2010).
The most frequently reported BRAF mutation is an activating missense mutation in which the amino acid glutamic acid is substituted for valine at amino acid position 600 (V600E) (Mao et al. 2011; Rizzo et al. 2010). This mutation is also associated with unresponsiveness to anti-EGFR therapy in wild type KRAS patients with mCRC, as indicated by the results of a meta-analysis by Mao et al. (2011).
While BRAF V600-mutated melanomas are sensitive to vemurafenib (Sosman et al. 2012), BRAF V600-mutated CRCs may not be as sensitive (Kopetz et al. 2010; Prahallad et al. 2012). Activation of EGFR in colorectal cancer could explain why colorectal cancers generally have a lower response to BRAF inhibitors (Corcoran et al. 2012; Prahallad et al. 2012).
Last Updated: June 1, 2012
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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