Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway
Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway
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DOI：
10.1158/1078-0432.ccr-08-0333
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发表时间：
2008-06-15
影响因子：
11.5
通讯作者：
Sebolt-Leopold, Judith S.
中科院分区：
文献类型：
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作者：
Sebolt-Leopold, Judith S.
在哺乳动物丝裂原活化蛋白激酶(MAPK)信号转导通路中，细胞外信号相关激酶(ERK)通路在肿瘤药物发现领域受到最大关注。由于其在促进增殖、存活和转移方面的中心作用，该途径直接影响人类肿瘤的形成和发展。MAPK/ERK激酶(MEK)的非ATP竞争性抑制物的发现首次证明ERK通路可以以高度选择性的方式被有效地关闭。随后发现的B-RAF激酶的致癌性质导致了围绕MEK和RAF的药物发现努力的升级。针对这些下游激酶的多个候选药物的出现为我们提供了验证RAS-RAF-MEK-ERK信号级联在人类肿瘤中的重要性的手段。本文重点介绍了MAPK途径抑制剂作为抗癌药物在临床评估中的经验教训，以及根据患者群体中遗传异质性带来的挑战优化其治疗潜力的复杂性。
Among mammalian mitogen-activated protein kinase (MAPK) signaling cascades, the extracellular signal-related kinase (ERK) pathway has received the most attention in the oncology drug discovery arena. By virtue of its central role in promoting proliferation, survival, and metastasis, this pathway directly affects both the formation and progression of human tumors. The identification of non-ATP-competitive inhibitors of the MAPK kinase MAPK/ERK kinase (MEK) resulted in the first demonstration that the ERK pathway could be effectively shut down in a highly selective fashion. Subsequent discovery of the oncogenic nature of B-raf kinase led to the escalation of drug discovery efforts revolving around MEK and RAF. The emergence of multiple drug candidates targeting these downstream kinases provides us with the means for validating the importance of the RAS-RAF-MEK-ERK signaling cascade in human tumors. This article highlights the lessons learned in the clinical evaluation of MAPK pathway inhibitors as anticancer agents and the complexities surrounding optimization of their therapeutic potential in light of the challenges posed by genetic heterogeneity within patient populations.