Department of Health Science, University of Eastern Piedmont, via Solaroli 17, 28100 Novara, Italy.
Section of Dermatology, Department of Medical Science, University of Turin, 10124 Turin, Italy.
Int J Mol Sci. 2019 Mar 25;20(6):1483. doi: 10.3390/ijms20061483.
The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.
RAS/RAF/MEK/ERK 通路在黑色素瘤发生和进展中的作用的发现开创了治疗这种肿瘤的新时代。维莫非尼是第一个被批准用于治疗携带 BRAF 激活突变的晚期黑色素瘤的特异性激酶抑制剂，随后是达拉非尼和恩考芬尼。然而，尽管第一代激酶抑制剂在反应率方面取得了优异的结果，但由于遗传和表观遗传耐药机制的出现，反应的平均持续时间很短。MEK 抑制剂的联合治疗是规避耐药性的一种很好的策略，由于 MAPK 通路的反常再激活，它还有减少副作用的额外优势。RAS 和细胞外信号相关激酶（ERK）抑制剂的最新发展有望为最终抑制这种信号通路和控制与通路相关的耐药性添加新的药物。在这篇综述中，我们分析了各种 MAPK 通路抑制剂的药理学、临床前和临床试验数据，特别关注它们在晚期黑色素瘤治疗中的临床应用。
