Reference Detail

Ref Type

Journal Article

PMID

(28947956)

Authors

Noeparast A, Teugels E, Giron P, Verschelden G, De Brakeleer S, Decoster L, De Grève J

Title

Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	8	36	2017 Sep 01	60094-60108	Oncotarget

URL

Abstract Text

Approximately half of BRAF-mutated Non-small cell lung cancers (NSCLCs) harbor a non-V600 BRAF mutation, accounting for ∼40,000 annual deaths worldwide. Recent studies have revealed the benefits of combined targeted therapy with a RAF-inhibitor (Dabrafenib) and a MEK-inhibitor (Trametinib) in treating V600 BRAF mutant cancers, including NSCLC. In contrast, sensitivity of non-V600 BRAF mutations to these inhibitors is not documented. Non-V600 mutations can either increase or impair BRAF kinase activity. However, impaired BRAF kinases can still activate the ERK pathway in a CRAF-dependent manner. Herein, beyond describing a cohort of BRAF mutant NSCLC patients and functionally analyzing 13 tumor-derived BRAF mutations, we demonstrate that both types of non-V600 BRAF mutations can be sensitive to clinically relevant doses of Dabrafenib and Trametinib in HEK293T cells, in lung epithelial cellular model (BEAS-2B) and in human cancer cell lines harboring non-V600 BRAF mutations. ERK activity induced by both types of these mutations is further reduced by combinatorial drug treatment. Moreover, the combination leads to more prolonged ERK inhibition and has anti-proliferative and pro-apoptotic effects in cells harboring both types of non-V600 BRAF mutations. This study provides a basis for the clinical exploration of non-V600 BRAF mutant lung cancers upon treatment with Trametinib and Dabrafenib.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
BRAF	D594V	missense	loss of function	BRAF D594V lies within the protein kinase domain of the Braf protein (UniProt.org). D594V results in impaired Braf kinase activity, and decreased activation of Erk, Mek, and CRAF in cell culture (PMID: 28947956, PMID: 15035987), and has decreased transforming ability in one of two cell lines compared to wild-type Braf in culture (PMID: 29533785).
BRAF	G469V	missense	gain of function	BRAF G469V is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469V results in increased Braf kinase activity and activation of downstream MEK and ERK in cell culture (PMID: 28947956, PMID: 26343582, PMID: 28783719), and in one of two cell lines, increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785).
BRAF	G596C	missense	loss of function	BRAF G596C lies within the protein kinase domain of the Braf protein (UniProt.org). G596C results in decreased Braf kinase activity, however, leads to activation of downstream MEK and ERK in combination with CRAF in cell culture (PMID: 28947956).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF G596R	colorectal cancer	sensitive	Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) resulted in decreased proliferation and increased apoptosis, and enhanced ERK inhibition compared to either agent alone in a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 28947956).	28947956
BRAF mutant	lung non-small cell carcinoma	predicted - sensitive	Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) resulted in decreased proliferation and increased apoptosis and enhanced ERK inhibition compared to either agent alone in non-small cell lung cancer cell lines harboring non-BRAF V600 mutations in culture (PMID: 28947956).	28947956
BRAF G469A	lung non-small cell carcinoma	sensitive	Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) resulted in decreased viability and enhanced ERK inhibition compared to either agent alone, in a non-small cell lung cancer cell line harboring BRAF G469A in culture (PMID: 28947956).	28947956
BRAF G466V	lung non-small cell carcinoma	sensitive	Dabrafenib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) resulted in decreased proliferation and increased apoptosis, and enhanced ERK inhibition compared to either agent alone in a non-small cell lung cancer cell line harboring BRAF G466V in culture (PMID: 28947956).	28947956