Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy
Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy
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DOI：
10.1016/j.isci.2020.101028
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发表时间：
2020-04-24
期刊：
影响因子：
5.8
通讯作者：
Tomida, Akihiro
中科院分区：
文献类型：
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作者：
Nagasawa, Ikuko;Koido, Masaru;Tomida, Akihiro
BRAF V600突变影响黑色素瘤发展的细胞信号通路。然而，致癌BRAF在适应性应激反应途径中的作用尚不完全清楚。在这里，我们发现在营养应激和BRAF靶向的治疗性应激中，致癌BRAF在诱导ATF4的过程中发挥了重要作用，随后激活了一般控制非抑制2 （GCN2）激酶。在GCN2激活下，BRAF通过mTOR和eIF4B作为下游调节因子来确保ATF4的诱导。与MEK-ERK通路相反，即使在BRAF抑制剂治疗期间，该信号通路仍保持暂时活性，从而能够短暂诱导ATF4。我们还发现了一种化合物，它可以阻止BRAF抑制剂诱导的GCN2-ATF4通路的激活，并与BRAF抑制剂产生协同细胞杀伤。我们的研究结果建立了致癌BRAF和GCN2-ATF4信号通路之间的协作关系，这可能为靶向适应性应激反应提供一种新的治疗方法。
BRAF V600 mutation 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.