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Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer

A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK sign...

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Autores principales: Noeparast, Amir, Giron, Philippe, De Brakeleer, Sylvia, Eggermont, Carolien, De Ridder, Ulrike, Teugels, Erik, De Grève, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882321/
https://www.ncbi.nlm.nih.gov/pubmed/29662630
http://dx.doi.org/10.18632/oncotarget.24576
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author Noeparast, Amir
Giron, Philippe
De Brakeleer, Sylvia
Eggermont, Carolien
De Ridder, Ulrike
Teugels, Erik
De Grève, Jacques
author_facet Noeparast, Amir
Giron, Philippe
De Brakeleer, Sylvia
Eggermont, Carolien
De Ridder, Ulrike
Teugels, Erik
De Grève, Jacques
author_sort Noeparast, Amir
collection PubMed
description A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK signaling and can induce ERK paradoxical activation in CRAF-overexpressing cells. The present study compared the effects of Dabrafenib and a type II RAF inhibitor, AZ628, on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants, and in a non-V600 and impaired-kinase BRAF-mutant lung cancer cell line (H1666). Unlike Dabrafenib, AZ628 did not induce paradoxical ERK activation in CRAF-overexpressing cells and BRAF-mutant cells overexpressing CRAF were more responsive to AZ628 compared to Dabrafenib in terms of ERK inhibition. AZ628 inhibited ERK more effectively than Dabrafenib in both H1666 cells and HEK293T cells co-expressing several different BRAF-mutants with CRAF. Similarly, AZ628 plus Trametinib had better MEK-inhibitory and pro-apoptotic effects in H1666 cells than Dabrafenib plus Trametinib. Moreover, prolonged treatment of H1666 cells with AZ628 plus Trametinib produced greater inhibition of cell growth than Dabrafenib plus Trametinib. These results indicate that AZ628 has greater potential than Dabrafenib, both as a single agent and combined with Trametinib, for the treatment of non-V600 BRAF mutant lung cancer.
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spelling pubmed-58823212018-04-16 Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer Noeparast, Amir Giron, Philippe De Brakeleer, Sylvia Eggermont, Carolien De Ridder, Ulrike Teugels, Erik De Grève, Jacques Oncotarget Research Paper A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK signaling and can induce ERK paradoxical activation in CRAF-overexpressing cells. The present study compared the effects of Dabrafenib and a type II RAF inhibitor, AZ628, on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants, and in a non-V600 and impaired-kinase BRAF-mutant lung cancer cell line (H1666). Unlike Dabrafenib, AZ628 did not induce paradoxical ERK activation in CRAF-overexpressing cells and BRAF-mutant cells overexpressing CRAF were more responsive to AZ628 compared to Dabrafenib in terms of ERK inhibition. AZ628 inhibited ERK more effectively than Dabrafenib in both H1666 cells and HEK293T cells co-expressing several different BRAF-mutants with CRAF. Similarly, AZ628 plus Trametinib had better MEK-inhibitory and pro-apoptotic effects in H1666 cells than Dabrafenib plus Trametinib. Moreover, prolonged treatment of H1666 cells with AZ628 plus Trametinib produced greater inhibition of cell growth than Dabrafenib plus Trametinib. These results indicate that AZ628 has greater potential than Dabrafenib, both as a single agent and combined with Trametinib, for the treatment of non-V600 BRAF mutant lung cancer. Impact Journals LLC 2018-02-27 /pmc/articles/PMC5882321/ /pubmed/29662630 http://dx.doi.org/10.18632/oncotarget.24576 Text en Copyright: © 2018 Noeparast et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Noeparast, Amir
Giron, Philippe
De Brakeleer, Sylvia
Eggermont, Carolien
De Ridder, Ulrike
Teugels, Erik
De Grève, Jacques
Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer
title Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer
title_full Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer
title_fullStr Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer
title_full_unstemmed Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer
title_short Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer
title_sort type ii raf inhibitor causes superior erk pathway suppression compared to type i raf inhibitor in cells expressing different braf mutant types recurrently found in lung cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882321/
https://www.ncbi.nlm.nih.gov/pubmed/29662630
http://dx.doi.org/10.18632/oncotarget.24576
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