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

Amir Noeparast,Erik Teugels,Philippe Giron,Lore Decoster,Sylvia De Brakeleer,Gil Verschelden,Jacques De Grève

doi:10.18632/oncotarget.11635

Abstract

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.

Highlights

BRAF mutations are found in ~8% of human cancers and occur in 6–8% of non-small cell lung cancers (NSCLCs) [1, 2]
Beyond describing a cohort of BRAF mutant Non-small cell lung cancers (NSCLCs) 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
This study provides a basis for the clinical exploration of non-V600 BRAF mutant lung cancers upon treatment with Trametinib and Dabrafenib

Summary

Introduction

BRAF mutations are found in ~8% of human cancers and occur in 6–8% of non-small cell lung cancers (NSCLCs) [1, 2]. V600 mutated BRAF has constitutively high kinase activity towards its downstream effector, mitogen/ extracellular signal-regulated kinase (MEK), which in turn results in strong activation of extracellular-signal-regulated kinase (ERK) [8]. High kinase activity towards MEK due to V600 mutations has been shown in non-cellular systems [6, 9, 10]. Some non-V600 BRAF mutations confer high kinase activity in cell-free assays, while other non-V600 mutations result in impaired kinase activity. Kinase-impairing BRAF mutations still induce ERK pathway activation when wild-type CRAF, a heterodimerization partner of BRAF, is present in the cell [9]

Methods

Results

Conclusion