NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3Kα
NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3Kα
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DOI：
10.1158/0008-5472.can-17-1737
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发表时间：
2018-04-15
期刊：
影响因子：
11.2
通讯作者：
Fulda, Simone
中科院分区：
文献类型：
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作者：
Dolgikh, Nadezda;Hugle, Manuela;Fulda, Simone
测序研究揭示了横纹肌肉瘤（RMS）中RAS通路的复发性突变。然而，RMS中的RAS效应通路定义不清。在这里，我们报告说，共抑制NRAS或MEK加PI 3 K α触发广泛的NRAS突变的RMS细胞凋亡。亚毒性浓度的MEK抑制剂MEK 162和PI 3 K α特异性抑制剂BYL 719协同作用，在体外和体内触发NRAS突变的RMS细胞凋亡。NRAS或HRAS突变的细胞系比RAS野生型细胞系更容易受到MEK 162/BYL 719共治疗的影响，并且MEK 162/BYL 719共治疗在体内NRAS突变的RMS肿瘤中比RAS野生型RMS肿瘤中更有效地触发细胞凋亡。我们确定BCL-2修饰因子（BMF）作为致癌NRAS的抑制靶标，NRAS沉默或MEK抑制上调BMF mRNA和蛋白水平，BYL 719进一步增加。BMF沉默消除了MEK 162/BYL 719诱导的细胞凋亡。机制研究涉及BCL-2家族成员的促凋亡再平衡和对MEK 162/BYL 719共处理后凋亡敏感性中的帽依赖性翻译的抑制。我们的研究结果提供了一个合理的结合MEK和PI 3 Ka特异性抑制剂在临床治疗RAS突变的RMS.Significance：这些研究结果提供了一个机械原理结合MEK和PI 3 Ka特异性抑制剂在临床治疗RAS突变的形式，往往无法治疗的横纹肌肉瘤。(C)2018年AACR。
Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3K alpha triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3K alpha-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS-or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo. We identified BCL-2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK-and PI3Ka-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK-and PI3Ka-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. (C) 2018 AACR.