eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies
eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies
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DOI：
10.1038/nature13572
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发表时间：
2014-09-04
期刊：
影响因子：
64.8
通讯作者：
Vagner, Stephan
中科院分区：
文献类型：
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作者：
Boussemart, Lise;Malka-Mahieu, Helene;Vagner, Stephan
在BRAF（V600）突变型肿瘤中，对靶向BRAF和/或MEK激酶的药物的大多数耐药机制依赖于RAS-RAF-MEK-ERK促分裂原活化蛋白激酶（MAPK）信号转导途径的再活化、替代途径PI（3）K-AKT-mTOR途径（不依赖于ERK）的活化或半胱天冬酶依赖性凋亡级联的调节（1-3）。所有这三种途径共同调节eIF 4F真核生物翻译起始复合物的形成，该复合物与信使RNA 59末端的7-甲基鸟苷酸帽（m（7）G）结合，从而调节特定mRNA的翻译（4，5）。在这里，我们表明，持续形成的eIF 4F复合物，包括eIF 4 E帽结合蛋白，eIF 4G支架蛋白和eIF 4A RNA解旋酶，与耐药性的抗BRAF，抗MEK和抗BRAF加抗MEK药物组合在BRAF（V600）突变的黑色素瘤，结肠癌和甲状腺癌细胞系。eIF 4F复合物形成对治疗和维持的抗性与以下三种机制之一相关：MAPK信号转导的再激活、抑制性eIF 4 E结合蛋白4 EBP 1的持续ERK非依赖性磷酸化或eIF 4G的促凋亡BCL-2修饰因子（BMF）依赖性降解增加。原位检测eIF 4 E-eIF 4G相互作用方法的开发表明，与治疗前的肿瘤相比，对抗BRAF治疗有反应的肿瘤中eIF 4F复合物形成减少，耐药转移增加。引人注目的是，通过阻断eIF 4 E-eIF 4G相互作用或通过靶向eIF 4A来抑制eIF 4F复合物与抑制BRAF（V600）协同杀死癌细胞。eIF 4F似乎不仅是先天性和获得性抗性的指标，而且是有希望的治疗靶点。靶向BRAF（和/或MEK）和eIF 4F的药物组合可以克服BRAF（V600）突变型癌症中出现的大多数耐药机制。
In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3) K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade(1-3). All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 59 end of messenger RNA, thereby modulating the translation of specific mRNAs(4,5). Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF(and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.