Targeting MEK for the treatment of non-small-cell lung cancer.
Targeting MEK for the treatment of non-small-cell lung cancer.
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DOI：
10.1097/jto.0b013e31826df0bc
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发表时间：
2012-12-01
期刊：
影响因子：
--
通讯作者：
Garon, Edward B
中科院分区：
文献类型：
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作者：
Goldman, Jonathan W;Garon, Edward B
抑制RAS/RAF/丝裂原活化蛋白激酶(MEK)/细胞外信号调节激酶（ERK）通路多年来一直是药物开发的重点。该通路在很大比例的实体肿瘤中失调，包括约20%至35%的非小细胞肺癌（NSCLC）。然而，很难成功地确定这一途径的目标。2 RAS抑制剂是该通路中最常见的突变基因，在临床试验中尚未产生成功的结果。因此，沿着该途径的其他点的抑制作用已被评估。MEK1和MEK2是苏氨酸/酪氨酸蛋白激酶，可被活化的RAF磷酸化，进而磷酸化ERK1和ERK2，导致增殖和迁移。在实验室模型中，RAS或RAF的突变导致持续的致癌信号，并预测对MEK抑制的反应。3,4在第12届肺癌靶向治疗年度会议上，我们介绍了三种MEK抑制剂和一种Akt抑制剂，并将在此进行综述。
Inhibition of the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has been the focus of drug development for many years. The pathway is dysregulated in a significant percentage of solid tumors, including approximately 20% to 35% of non–small-cell lung cancers (NSCLC). 1 Nevertheless, successful targeting of this pathway has been difficult to achieve. 2 Inhibitors of RAS, the most commonly mutated gene in this pathway, have not generated successful results in clinical trials. Therefore, inhibition at other points along the pathway has been evaluated.MEK1 and MEK2 are threonine/tyrosine protein kinases that are phosphorylated by activated RAF and in turn, phosphorylate ERK1 and ERK2, leading to proliferation and migration. Mutations in RAS or RAF lead to a sustained oncogenic signal and predict response to MEK inhibition in laboratory models. 3, 4 Three MEK inhibitors and an Akt inhibitor were presented in this session at the 12th Annual Targeted Therapies of the Treatment of Lung Cancer and will be reviewed here.