• What is BRAF?
  • BRAF in Melanoma
  • Clinical Trials


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). Mutant BRAF has been observed in these cancers as well as glioma and gastrointestinal stromal tumor (GIST).


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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. BRAF. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BRAF in Melanoma

Somatic mutations in BRAF have been found in 37-50% of all malignant melanomas (COSMIC; Davies et al. 2002; Hodis et al. 2012; Krauthammer et al. 2012; Maldonado et al. 2003). BRAF mutations are found in all melanoma subtypes but are the most common in melanomas derived from skin without chronic sun-induced damage (Curtin et al. 2005; Maldonado et al. 2003). In this category of melanoma, BRAF mutations are found in ~59% of samples (Curtin et al. 2005).

The most prevalent BRAF mutations detected in melanoma are missense mutations that introduce an amino acid substitution at valine 600. Approximately 80–90% of V600 BRAF mutations are V600E (valine to glutamic acid; COSMIC; Lovly et al. 2012; Rubinstein et al. 2010) while 5-12% are V600K (valine to lysine; COSMIC; Lovly et al. 2012; Rubinstein et al. 2010), and 5% or less are V600R (valine to arginine) or V600D (valine to aspartic acid; COSMIC;Lovly et al. 2012; Rubinstein et al. 2010). The result of these mutations is enhanced BRAF kinase activity and increased phosphorylation of downstream targets, particularly MEK (Wan et al. 2004). In the vast majority of cases, BRAF mutations are non-overlapping with other oncogenic mutations found in melanoma (e.g., NRAS mutations, KIT mutations, etc.).

While BRAF inhibitor therapy is associated with clinical benefit in the majority of patients with BRAF V600E- mutated melanoma, resistance to treatment and tumor progression occurs in nearly all patients, usually in the first year (Chapman et al. 2011; Sosman et al. 2012). A variety of mechanisms have been implicated in primary and acquired resistance to BRAF inhibitors, primarily through reactivation of the MAP kinase pathway and other cell signaling pathways. Secondary BRAF mutations have not been described. Mechanisms of resistance are described below (Table 1); the frequencies of each of these mechanisms of resistance are not yet known. Possible second-line and greater treatment options supported by preclinical rationale are listed, although clinical data are mostly lacking. First-line combination therapy with BRAF and MEK inhibitor therapy may delay or prevent some of the mechanisms below (Flaherty et al. 2012). Additionally, BRAF inhibitors have been investigated in combination with MEK inhibitors in subsets of patients with BRAF V600E-mutated melnaoma previously resistant to BRAF inhibitors (Johnson et al. 2014; Ribas et al. 2014).

Table 1. Mechanisms of Resistance to BRAF Inhibition.

Mechanism of resistance Implications for Targeted Therapeutics
BRAF V600 alternate splicing Unknown at this timea
BRAF V600 gene amplification Unknown at this timeb
COT overexpression Unknown at this timec
CRAF overexpression Unknown at this timed
HGF overexpression Unknown at this timee
IGF1R overexpression Unknown at this timef
Acquired MEK1 (MAP2K1) mutations Unknown at this timeg
NF1 loss of function (via mutation, deletion, etc.) Unknown at this timeh
Acquired NRAS mutations Unknown at this timei
PDGFRβ overexpression Unknown at this timej
PI3K/AKT1 mutations Unknown at this timek
PTEN loss Unknown at this timel


a See Poulikakos et al. 2011.

b See Shi H. et al. 2012.

c In preclinical studies, cell lines overexpressing COT (the product of the MAP3K8 gene) were sensitive to combinations of BRAF and MEK inhibitors but resistant to BRAF or MEK inhibitors alone (Johannesson et al. 2010).

d A BRAF inhibitor–resistant cell line demonstrating CRAF (the product of the RAF1 gene) overexpression was sensitive to the HSP inhibitor geldanamycin in preclinical studies (Montagut et al. 2008).

e In preclinical studies, cell lines overexpressing HFG were sensitive to combinations of BRAF and HGF inhibitors and combinations of BRAF and MET inhibitors (Straussman et al. 2012; Wilson et al. 2012).

f In preclinical studies, cell lines overexpressing IGF1R were sensitive to combinations of MEK and IGF1R inhibitors and combinations of MEK and PI3K inhibitors (Villanueva et al. 2010).

g See Emery et al. 2009 and Wagle et al. 2011.

h See Gibney and Smalley 2013; Maertens et al. 2013; Nissan et al. 2014; Whittaker et al. 2013.

i NRAS Q61K mutations resulted in increased levels of activated NRAS in two cell lines. These cell lines were sensitive to MEK inhibition with AZD6244 in preclinical studies (Nazarian et al. 2010).

j See Nazarian et al. 2010.

k See Shi et al. 2014 and Van Allen et al. 2014. l See Paraiso et al. 2011.

Contributors: Christine M. Lovly, M.D., Ph.D., Douglas Johnson, M.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.

Suggested Citation: Lovly, C., D. Johnson, W. Pao, J. Sosman. 2015. BRAF in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/braf/ (Updated June 16).

Last Updated: June 16, 2015

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