• What is BRAF?
  • BRAF in Colorectal Cancer
  • BRAF c.1781A>T (D594V)
  • 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.1781A>T (D594V) 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 D594V mutations among BRAF-mutated colorectal cancers <0.1% (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 time
Response to mutant-specific BRAF inhibitors Unknown at this time
Response to combination of BRAF and EGFR inhibitors Unknown at this time
Response to combination of BRAF inhibitors with other therapies Unknown at this time

The D594V mutation results in an amino acid substitution at position 594 in BRAF, from an aspartic acid (D) to a valine (V). This mutation occurs within the kinase domain (Figure 1). Most mutant BRAF proteins have increased kinase activity and are transforming in vitro (Davies et al. 2002). However, the BRAF D594V mutant actually demonstrates reduced in vitro kinase activity (Ikenoue et al. 2003; Wan et al. 2004). The D594V mutation was first reported by Yuen et al. (2002), in a tumor sample that was also positive for a KRAS mutation.

a BRAF mutations are thought to confer de novo resistance to EGFR antibodies (Bardelli and Janne 2012).

BRAF_D594V.png

Figure 1.
Schematic of BRAF D594V mutation. Functional domains of BRAF are depicted. CR1: conserved regions 1. CR2: conserved region 2.

Contributors: Daniel G. Stover, M.D.

Suggested Citation: Stover, D. 2015. BRAF c.1781A>T (D594V) Mutation in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/braf/149/ (Updated February 18).

Last Updated: February 18, 2015

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