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.

中文翻译：

---

MEK/ERK 网络作为人类癌症的治疗靶点

RAS-RAF-MEK-ERK 途径是研究最深入的丝裂原激活蛋白激酶 (MAPK) 级联，对于细胞增殖、分化和存活至关重要。该通路各组成部分（尤其是上游蛋白 RAS 和 RAF）突变导致的调节异常是导致大部分人类癌症和几乎所有皮肤黑色素瘤的原因。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，在通路激活异常的情况下，激活大量转录因子并促进肿瘤发生。虽然广泛的研究致力于阐明上游 MAPK 成分的激活机制和结构成分，但由于这些激酶中致癌激活突变的频率较低，因此对 MEK 和 ERK 激酶的关注相对较少。然而，获得性耐药已成为 RAS 和 RAF 突变癌症治疗的主要问题。以 MAPK 级联中的末端激酶为目标，有望克服许多耐药机制，并改善 MAPK 异常癌症患者的治疗选择。在这里，我们将描述 MEK 和 ERK 在 MAPK 信号传导中的作用，并总结目前对其相互作用和激活机制的理解。我们还将讨论 MEK 和 ERK 的现有针对性方法，以及替代策略的好处。将重点关注需要进一步探索的领域，以指导未来的研究工作，并帮助开发替代治疗策略，以对抗 MAPK 介导的癌症治疗中克服的耐药性。