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.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. BRAF. My Cancer
(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;
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.).
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.1799T>A (V600E) Mutation in Non-Small Cell Lung Cancer
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,
such as V600E, 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. 2009; Pratilas et al. 2008).
It should also be noted that BRAF mutations are usually found in tumors
wild type for EGFR, ALK, and other driver mutations.
b At this time, there are case reports of patients whose non-small cell
lung cancer tumor harbored a BRAF V600E (c.1799T>A) mutation
that responded to vemurafenib (Gautschi et al. 2012) or dabrafenib
(Rudin et al. 2013),
respectively. Thus far, vemurafenib is FDA-approved for use only in BRAF V600E-mutated
melanoma, and dabrafenib has also shown highly promising activity in that disease (BRAF V600E Mutation in
c The FDA has approved use of the combination therapy dabrafenib and
trametinib for melanoma patients with V600E or V600K mutations
based on the results of the Study BRF113928, an international, multicenter, three-cohort,
non-randomized, non-comparative, open-label, trial in patients with locally confirmed BRAF
V600E mutation-positive metastatic NSCLC. The patients treated with the combination therapy
had a significantly higher overall response rate (ORR) compared to the patients treated with
single-agent dabrafenib (Planchard et
al. 2017; FDA 2017).
d In preclinical studies, lung cancer cell lines harboring the
BRAF V600E mutation were not sensitive to
dasatinib (Sen et al.
||Study Type / Phase
||Line of Treatment
||# Patients in Study
et al. 2017
||1st or greater
||dabrafenib + trametinib
||66% at 12 months
||52% at 12 months
NOTE: PFS = progression-free survival; OS = overall survival; TTD = time to death; TTP
= time to progression.
Figure 1. Schematic of BRAF V600E mutation. Functional domains of BRAF are
depicted. CR1: conserved regions 1. CR2: conserved region 2.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2017. BRAF c.1799T>A (V600E)
Mutation in Non-Small Cell Lung Cancer. My
Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/braf/54/
(Updated September 20).
Last Updated: September 20, 2017
My Cancer Genome has released its new and improved cancer clinical trials search tool on our
beta website. Please visit beta.padiracinnovation.org
to check it out!