The MEK/ERK Network as a Therapeutic Target in Human Cancer.
The MEK/ERK Network as a Therapeutic Target in Human Cancer.
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DOI：
10.1158/1541-7786.mcr-20-0687
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Marmorstein R
中科院分区：
文献类型：
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作者：
Barbosa R;Acevedo LA;Marmorstein R
RAS-RAF-MEK-ERK通路是丝裂原活化蛋白激酶（MAPK）级联中研究最充分的通路，对细胞增殖、分化和存活至关重要。由该途径的组分中的突变引起的调节缺失，特别是在上游蛋白RAS和RAF中，是相当一部分人类癌症和几乎所有皮肤黑色素瘤的原因。通过生长因子和各种细胞外信号激活受体酪氨酸激酶，依次激活RAS、RAF、MEK，最后激活ERK，其激活许多转录因子并在异常途径激活的情况下促进肿瘤发生。虽然广泛的研究已致力于阐明上游MAPK组分的激活机制和结构组分，但由于这些激酶中致癌激活突变的频率不高，因此对激酶MEK和ERK的关注相对较少。然而，获得性耐药性已成为治疗RAS和RAF突变癌症的主要问题。靶向MAPK级联中的末端激酶已显示出克服许多这些耐药机制和改善MAPK异常癌症患者的治疗选择的前景。本文主要介绍MEK和ERK在MAPK信号转导中的作用，并对它们的相互作用和激活机制进行综述。我们还将讨论MEK和ERK的现有靶向方法，以及替代策略的好处。需要进一步探索的领域将被强调，以指导未来的研究工作，并帮助开发替代治疗策略，以克服治疗MAPK介导的癌症的耐药性。显示的是MAPK途径的概述，强调了激活和磷酸化的各种机制，以及寡聚化和反馈调节的重要性。问号表示本模型中的不确定区域，箭头表示顺序激活和信号传输步骤。
The RAS-RAF-MEK-ERK pathway is the most well-studied of the mitogen-activated protein kinase (MAPK) cascades and is critical for cell proliferation, differentiation, and survival. Abnormalities in regulation resulting from mutations in components of this pathway, particularly in upstream proteins RAS and RAF, are responsible for a significant fraction of human cancers and nearly all cutaneous melanomas. Activation of receptor tyrosine kinases by growth factors and various extracellular signals to the sequential activation of RAS, RAF, MEK, and finally ERK, which activates numerous transcription factors and facilitates oncogenesis in the case of aberrant pathway activation. While extensive studies have worked to elucidate the activation mechanisms and structural components of upstream MAPK components, comparatively less attention has been directed towards the kinases, MEK and ERK, due to the infrequency of oncogenic activating mutations in these kinases. However, acquired drug resistance has become a major issue in the treatment of RAS- and RAF- mutated cancers. Targeting the terminal kinases in the MAPK cascade has shown promise for overcoming many of these resistance mechanisms and improving treatment options for patients with MAPK-aberrant cancers. Here, we will describe the role of MEK and ERK in MAPK signaling and summarize the current understanding of their interaction and activation mechanisms. We will also discuss existing targeted approaches for MEK and ERK, and the benefits of alternative strategies. Areas requiring further exploration will be highlighted to guide future research endeavors and aid in the development of alternative therapeutic strategies to combat surmounting drug resistance in treating MAPK-mediated cancers. Shown is an overview of the MAPK pathway highlighting the various mechanisms of activation and phosphorylation, as well as the importance of oligomerization and feedback regulation. Question marks indicate areas of uncertainty in the present model and arrows show sequential activation and signal transmission steps.