Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata, IRCCS, 00167 Rome, Italy.
Int J Mol Sci. 2017 Oct 24;18(10):2227. doi: 10.3390/ijms18102227.
Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash. Here, we investigated the response of normal human keratinocytes to the MEK inhibitors trametinib and cobimetinib, alone and in combination with the v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors dabrafenib and vemurafenib, in terms of signal transduction and de novo gene expression. MEK inhibitors triggered enhanced expression of interferon regulatory factor 1 (IRF1) and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and up-regulated the keratinocyte-specific type I interferon κ (IFN-κ), the anti-viral effectors interferon-induced tetratricopeptide repeats (IFIT) 1 and 2, and the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) and the C-X-C motif chemokine 10 (CXCL10), both at the mRNA and protein level. Impairment of IRF1 expression, or abrogation of STAT1 phosphorylation due to gene silencing, suppressed anti-viral and pro-inflammatory gene expression. These data suggest that, similar to what we observed for epidermal growth factor receptor (EGFR) blockade, MEK inhibition activates a type I interferon response, which is now recognized as an effective anti-cancer response, in human epidermal keratinocytes.
丝裂原活化蛋白激酶激酶（MEK）1 和 2 在肿瘤发生、细胞增殖和细胞凋亡保护中起着至关重要的作用，因此其抑制作用是癌症治疗的一种有吸引力的策略。口服可用且高度选择性的 MEK 抑制剂已被开发并在许多临床试验中进行了评估，无论是单独使用还是与细胞毒性化疗和/或其他靶向药物联合使用。值得注意的是，这些药物与特定类别的不良反应相关，包括炎症性皮疹。在这里，我们研究了 MEK 抑制剂曲美替尼和考比替尼单独使用和与 v-Raf 鼠肉瘤病毒致癌基因同源物 B（BRAF）抑制剂达拉非尼和维莫非尼联合使用时，对正常人类角质形成细胞信号转导和从头基因表达的影响。MEK 抑制剂触发干扰素调节因子 1（IRF1）的增强表达和信号转导和转录激活因子 1（STAT1）的磷酸化，并上调角质形成细胞特异性 I 型干扰素 κ（IFN-κ）、抗病毒效应物干扰素诱导的四肽重复（IFIT）1 和 2 以及促炎趋化因子（C-C 基元）配体 2（CCL2）和 C-X-C 基元趋化因子 10（CXCL10），在 mRNA 和蛋白质水平上。IRF1 表达的抑制或基因沉默导致 STAT1 磷酸化的破坏，抑制了抗病毒和促炎基因的表达。这些数据表明，类似于我们观察到的表皮生长因子受体（EGFR）阻断，MEK 抑制在人类表皮角质形成细胞中激活 I 型干扰素反应，这现在被认为是一种有效的抗癌反应。
