Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes
Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes
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DOI：
10.1016/j.ccell.2015.07.001
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发表时间：
2015-08-10
期刊：
影响因子：
50.3
通讯作者：
Crespo, Piero
中科院分区：
文献类型：
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作者：
Herrero, Ana;Pinto, Adan;Crespo, Piero
近50%的人类恶性肿瘤表现出不调节的RAS-ERK信号；抑制它是一种有效的抗肿瘤干预策略。激活后，ERK二聚化，这是ERK核外信号所必需的，但不是核信号。在这里，我们描述了一种ERK二聚化的小分子抑制剂，它在不影响ERK磷酸化的情况下，阻止了RAS-ERK途径致癌基因驱动的肿瘤发生。该化合物不受阻碍经典RAS-ERK途径抑制剂的耐药机制的影响。因此，ERK二聚化抑制剂为癌症治疗中两个未被充分研究的概念提供了原理证明：(1)阻断亚定位特异性亚信号，而不是总信号，作为阻碍致癌RAS-ERK信号传导的手段；(2)靶向调节蛋白-蛋白相互作用，而不是催化活性，作为产生有效抗肿瘤药物的方法。
Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.