Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development
Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development
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DOI：
10.1093/neuonc/noz002
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发表时间：
2019-04-01
期刊：
影响因子：
15.9
通讯作者：
Fernandez-Valle, Cristina
中科院分区：
文献类型：
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作者：
Fuse, Marisa A.;Dinh, Christine T.;Fernandez-Valle, Cristina
研究背景2型神经纤维瘤病（NF 2）是一种由NF 2/merlin抑癌基因失活引起的遗传性肿瘤易感性疾病。NF 2的标志是形成双侧前庭神经鞘瘤（VS）。由于梅林调节活性的Ras/Raf/丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）通路，我们研究了再利用药物靶向MEK 1和/或MEK 2作为治疗NF 2相关的神经鞘瘤。在原位同种异体移植和NF 2转基因小鼠模型中测试有效药物。进行通路和蛋白质组分析。药物疗效进行了检查，在原代人VS细胞与NF 2突变和DNA甲基化patterns.Results曲美替尼，PD 0325901，cobimetinib是最有效的减少MD-MSC/HSC的活力。每一种都降低了磷酸化的pERK 1/2和细胞周期蛋白D1，增加了p27，并诱导了MD-MSC中的caspase-3裂解。蛋白质组学分析证实了曲美替尼处理的MD-MSC中的细胞周期停滞和促凋亡途径的激活。3种抑制剂减缓同种异体移植物生长;然而，仅在PD 0325901和cobimetinib处理的移植物中观察到pERK 1/2、细胞周期蛋白D1和Ki-67水平降低。曲美替尼处理的NF 2转基因小鼠的肿瘤负荷和平均肿瘤大小降低;然而，肿瘤未表现出pERK 1/2水平降低。曲美替尼和PD 0325901适度降低了几种具有NF 2突变的原代人VS细胞培养物的活力。PD 0325901耐药VS与敏感VS的DNA甲基化分析确定了可能导致耐药的基因。结论MEK抑制剂在神经鞘瘤模型中表现出抗肿瘤疗效的差异，可能出现曲美替尼耐药。结果支持进一步研究MEK抑制剂与其他靶向药物联合治疗NF 2神经鞘瘤。
Background Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas.Methods Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns.Results Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance.Conclusion MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.