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
|Location of mutation||Kinase domain (exon 15)|
|Frequency of BRAF mutations in colorectal cancer||8–15% (De Roock et al. 2009; Rizzo et al. 2010; Tejpar et al. 2010)|
|Frequency of V600E mutations among BRAF mutant colorectal cancers||47-96% (COSMIC)|
|Implications for Targeted Therapeutics|
|Response to EGFR TKIs||Unknown at this time|
|Response to anti-EGFR antibodies||Unknown at this timea|
|Response to BRAF inhibitors||Unknown at this timeb|
|Response to mutant-specific BRAF inhibitors||Unknown at this time|
|Response to combination of BRAF and EGFR inhibitors||Unknown at this timec|
|Response to combination of BRAF inhibitors with other therapies||Unknown at this timec|
The V600E mutation results in an amino acid substitution at position 600 in BRAF, from a valine (V) to a glutamic acid (E). This mutation occurs within the activation segment of the kinase domain (Figure 1). Most mutant BRAF proteins have increased kinase activity and are transforming in vitro (Davies et al. 2002).
a Most studies indicate that the BRAF V600E mutation negatively impacts treatment outcomes for anti-EGFR monoclonal antibodies in mCRC patients with KRAS wild-type tumors (De Roock et al. 2011; Mao et al. 2011; Tol et al. 2010).
b Several BRAF inhibitors, including vemurafenib (PLX4032) and others, are currently in clinical trials for cancer treatment, some of which include mCRC patients. (Dienstmann and Tabernero 2011; Kopetz et al. 2010). While BRAF V600-mutated melanomas are sensitive to vemurafenib, 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). Information from clinical investigations of anti-EGFR monoclonal antibodies in BRAF-mutant colorectal cancers is listed below in a table.
c In preclinical models, combination therapy with BRAF and EGFR inhibitors may be beneficial (Corcoran et al. 2012). BRAF-mutant colorectal cancer cell lines (Prahallad et al. 2012) and BRAF V600E-mutant xenografts (Yang et al. 2012) were shown to be sensitive to the BRAF inhibitor vemurafenib in combination with gefitinib (Prahallad et al. 2012), cetuximab, or erlotinib (Prahallad et al. 2012; Yang et al. 2012).
|Reference||Study Type / Phase||Line of Treatment||Treatment Agent||Mutation Status||# patients in study||Response Rate||PFS||OS|
|Mao et al. 2011||Meta-analysis||1st line or greater||Cetuximab, panitumumab, or cetuximab and chemotherapy||wtKRAS, BRAF V600||40||0.0%|
|Unknown KRAS, BRAF V600E||48||29.2%|
|Unknown KRAS, wtBRAF||472||33.5%|
|De Roock et al. 2010||Retrospective analysis||1st line or greater||Cetuximab plus chemotherapy||wtKRAS, BRAF mutant||24||8.3%||8 weeks||26 weeks|
|wtBRAF||326||38.0%||26 weeks||54 weeks|
|Tol et al. 2010||Retrospective analysis||1st line||Cetuximab, capecitabine, oxaliplatin, and bevacizumab||BRAF V600E||27||6.5 months||12.9 months|
|wtBRAF||126||11.4 months||24.5 months|
|Capecitabine, oxaliplatin, and bevacizumab||BRAF V600E||17||5.7 months||12.8 months|
|wtBRAF||126||10.8 months||23.0 months|
|Souglakos et al. 2009||Retrospective analysis||Second line or greater||Cetuximab and chemotherapy||BRAF mutant||9||0.0%||2 months|
|Van Cutsem et al. 2011||Retrospective analysis of phase II CRYSTAL trial||1st line||FOLFIRI and cetuximab||wtKRAS, BRAF V600E||26||8.0 months||14.1 months|
|wtKRAS, wtBRAF||277||10.9 months||25.1 months|
|FOLFIRI||wtKRAS, BRAF V600E||33||5.6 months||10.3 months|
|wtKRAS, wtBRAF||289||8.8 months||21.6 months|
Figure 1. Schematic of BRAF V600E mutation. Functional domains of BRAF are depicted. CR1: conserved regions 1. CR2: conserved region 2.
Last Updated: March 25, 2013
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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