• What is BRAF?
  • BRAF in Lung Cancer
  • BRAF c.1415A>G (Y472C)
  • 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/lung-cancer/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BRAF in Non-Small Cell Lung Cancer (NSCLC)

Somatic mutations in BRAF have been found in 1–4% of all NSCLC (Brose et al. 2002; Cardarella et al. 2013; Davies et al. 2002; Naoki et al. 2002; Paik et al. 2011; Pratilas et al. 2008), most of which are adenocarcinomas. BRAF mutations are more likely to be found in former/current smokers (Paik et al. 2011; Pratilas et al. 2008)

In contrast to melanoma where the majority of BRAF mutations occur at valine 600 (V600) within exon 15 of the kinase domain, BRAF mutations in lung cancer also occur at other positions within the kinase domain. In one study of 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%). Of these 18 patients, the BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%; Paik et al. 2011).

In the vast majority of cases, BRAF mutations are non-overlapping with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, ALK rearrangements, etc.).

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 in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/braf/ (Updated June 18).

Last Updated: June 18, 2015

BRAF c.1415A>G (Y472C) Mutation in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exon 11)
Frequency of BRAF mutations in NSCLC 1–4% (Brose et al. 2002; Cardarella et al. 2013; Davies et al. 2002; Naoki et al. 2002; Paik et al. 2011; Pratilas et al. 2008)
Frequency of Y472C mutations in BRAF-mutated NSCLC One case reported (Sen et al. 2012)
Implications for Targeted Therapeutics
Response to EGFR TKIs Unknown at this timea
Response to anti-EGFR antibodies Unknown at this time​
Response to BRAF inhibitors Unknown at this time
Response to MEK inhibitors Unknown at this time
Response to dasatinib Confers increased sensitivityb

The Y472C mutation results in an amino acid substitution at position 472 in BRAF, from a tyrosine (Y) to a cysteine (C). This mutation occurs within the kinase domain of BRAF (Figure 1). Most mutant BRAF proteins have increased kinase activity and are transforming in vitro (Davies et al. 2002​). Others have significantly reduced kinase activity, such as BRAF G466V​ and Y472C​ (Sen et al. 2012).

a Mutations giving rise to BRAF proteins with increased kinase activity have been associated with decreased sensitivity to gefitinib (Gandhi et al. 2009Pratilas et al. 2008). It should also be noted that BRAF mutations are usually found in tumors wild type for EGFRALK, and other driver mutations.

b A patient with a BRAF Y472C mutation, no common mutations in BRAF, EGFR or KRAS, and no ALK rearrangement responded to dasatinib, and the patient’s cancer has been inactive with no additional treatment for four years (Sen et al. 2012).

BRAF_Y472C.png

Figure 1. Schematic of BRAF Y472C mutation. Functional domains of BRAF are depicted. CR1: conserved regions 1. CR2: conserved region 2.

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Contributors: Faye M. Johnson, M.D., Ph.D.

Suggested Citation: Johnson, F. 2015. BRAF c.1415A>G (Y472C) Mutation in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/braf/209/ (Updated February 18).

Last Updated: February 18, 2015

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