• What is BRAF?
  • BRAF in Lung 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/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.1799T>A (V600E) Mutation in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exon 15)
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 V600E mutations in BRAF-mutated NSCLC 55% (COSMIC)
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 Confers increased sensitivityb
Response to MEK inhibitors Unknown​ at this time
Response to dabrafenib-trametinib combination therapy Confers increased sensitivityc
Response to dasatinib Unknown at this timed

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. 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 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 Melanoma).

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. 2017FDA 2017).

d In preclinical studies, lung cancer cell lines harboring the BRAF V600E mutation were not sensitive to dasatinib (Sen et al. 2012​).

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # Patients in Study Response Rate PFS OS
Planchard et al. 2017 Phase 2 1st or greater dabrafenib + trametinib V600E 57 67% 10.2 66% at 12 months
dabrafenib V600E 78 32% 5.5 52% at 12 months

​NOTE: PFS = progression-free survival; OS = overall survival; TTD = time to death; TTP = time to progression.

 

braf-v600e.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: 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. 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

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