Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers
Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers
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DOI：
10.1038/nature12441
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发表时间：
2013-09-12
期刊：
影响因子：
64.8
通讯作者：
Belvin, Marcia
中科院分区：
文献类型：
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作者：
Hatzivassiliou, Georgia;Haling, Jacob R.;Belvin, Marcia
KRAS和BRAF激活突变通过MAPK通路的组成性激活驱动肿瘤发生。由于这些肿瘤代表了一个高度未满足的医疗需求领域，多种抑制两种基因型MAPK信号的变构MEK抑制剂正在临床试验中进行测试。在braf突变黑色素瘤中观察到令人印象深刻的单药活性；然而，在kras突变疾病中，疗效远没有那么强(1)。在这里，我们表明，由于在kras与braf驱动的肿瘤中调节MEK激活的机制不同（2,3），每种基因型的最佳抗肿瘤活性需要不同的抑制机制。结构和功能分析表明，在kras驱动的肿瘤中具有卓越疗效的MEK抑制剂（GDC-0623和G-573，前者目前处于I期临床试验中）与MEK中的S212形成强烈的氢键相互作用，这对于阻断野生型RAF的MEK反馈磷酸化至关重要。相反，在braf突变肿瘤中，有效抑制活性磷酸化的MEK是对MAPK通路的强抑制所必需的，这导致GDC-0973（也称为cobimetinib）对该基因型具有优越的疗效，GDC-0973是一种MEK抑制剂，目前处于III期临床试验中。我们的研究强调了kras突变肿瘤与braf突变肿瘤中MEK激活状态的差异，可以通过设计独特靶向这些不同MEK激活状态的抑制剂来利用。这些抑制剂目前正在临床试验中进行评估，以确定KRAS与BRAF临床前模型中治疗指数的改善是否转化为患者临床反应的改善。
KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease(1). Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS-versus BRAF-driven tumours(2,3), different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.