• What is BRAF?
  • BRAF in Colorectal Cancer
  • BRAF c.1799T>A (V600E)
  • Clinical Trials

BRAF

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).

mapk-pk13.png

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/colorectal-cancer/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BRAF in Colorectal Cancer

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).​

Contributors: Daniel G. Stover, M.D.

Suggested Citation: Stover, D. 2015. BRAF in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/braf/ (Updated June 18).

Last Updated: June 18, 2015

BRAF c.1799T>A (V600E) Mutation in Colorectal Cancer

Properties
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-mutated 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-mutated 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-mutated colorectal cancer cell lines (Prahallad et al. 2012) and BRAF V600E-mutated 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%
wtKRAS, wtBRAF 336 36.3%
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
wtBRAF 83 17% 3.9 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
NOTE: PFS = progression-free survival; OS = overall survival.

BRAF_V600E_new.png

Figure 1.
Schematic of BRAF V600E mutation. Functional domains of BRAF are depicted. CR1: conserved regions 1. CR2: conserved region 2.

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Contributors: Daniel G. Stover, M.D.

Suggested Citation: Stover, D. 2015. BRAF c.1799T>A (V600E) Mutation in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/braf/54/ (Updated March 6).

Last Updated: March 6, 2015

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