文章基本信息

标题：Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy
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作者：Ikuko Nagasawa ; Masaru Koido ; Yuri Tani 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：4
页码：1-36
DOI：10.1016/j.isci.2020.101028
语种：English
出版社：Elsevier
摘要：SummaryBRAF V600mutation influences cellular signaling pathways for melanoma development. However, the role of oncogenic BRAF in adaptive stress response pathways is not fully understood. Here, we show that oncogenic BRAF plays an essential role in the induction of ATF4 following the activation of general control non-derepressible 2 (GCN2) kinase during nutrient stress and BRAF-targeted, therapeutic stress. Under GCN2 activation, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators. In contrast to the MEK-ERK pathway, this signaling pathway remains temporarily active even during treatment with BRAF inhibitors, thereby enabling the transient induction of ATF4. We also identify a chemical compound that prevents BRAF inhibitor-induced activation of the GCN2-ATF4 pathway and produces synergistic cell killing with BRAF inhibitors. Our findings establish a collaborative relationship between oncogenic BRAF and the GCN2-ATF4 signaling pathway, which may provide a novel therapeutic approach to target the adaptive stress response.Graphical AbstractDisplay OmittedHighlights•Oncogenic BRAF signals mTOR and eIF4B to ensure ATF4 induction under GCN2 activation•The signaling pathway decays relatively slowly during BRAF kinase inhibition•The slow signaling decay enables adaptive response via the GCN2-ATF4 pathway•The GCN2-ATF4 activation mechanisms by BRAF inhibitors may provide druggable targetsBiological Sciences; Molecular Biology; Cancer