神经纤维瘤病 2 型相关神经鞘瘤的 MEK1/2 抑制剂的临床前评估显示出疗效和耐药性发展的差异。
Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development.
机构信息
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida (UCF), Orlando, Florida, USA.
Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA.
出版信息
Neuro Oncol. 2019 Mar 18;21(4):486-497. doi: 10.1093/neuonc/noz002.
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.
背景
神经纤维瘤病 2 型（NF2）是一种由 NF2/ Merlin 肿瘤抑制基因失活引起的遗传性肿瘤易感性疾病。NF2 的标志是双侧前庭神经鞘瘤（VS）的形成。由于 Merlin 调节 Ras/Raf/丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）通路的活性，我们研究了重新利用针对 MEK1 和/或 MEK2 的药物作为 NF2 相关雪旺细胞瘤的治疗方法。
方法
用 6 种 MEK1/2 抑制剂对小鼠和人 Merlin 缺陷雪旺细胞系（MD-MSC/HSC）进行筛选。在同种异体移植和 NF2 转基因小鼠模型中测试有效的药物。进行了通路和蛋白质组分析。在具有 NF2 突变的原发性人 VS 细胞中检查了药物的疗效，并与 DNA 甲基化模式相关。
结果
曲美替尼、PD0325901 和 cobimetinib 在降低 MD-MSC/HSC 活力方面最有效。每种药物均降低了 MD-MSCs 中磷酸化的 pERK1/2 和 cyclin D1，增加了 p27，并诱导 caspase-3 切割。蛋白质组分析证实了曲美替尼处理的 MD-MSCs 中的细胞周期停滞和促凋亡途径的激活。这 3 种抑制剂均减缓了同种异体移植物的生长，但仅在 PD0325901 和 cobimetinib 处理的移植物中观察到 pERK1/2、cyclin D1 和 Ki-67 水平降低。在曲美替尼治疗的 NF2 转基因小鼠中，肿瘤负担和平均肿瘤大小减少，但肿瘤中未观察到 pERK1/2 水平降低。曲美替尼和 PD0325901 轻度降低了几种具有 NF2 突变的原发性人 VS 细胞培养物的活力。PD0325901 耐药性与敏感性 VS 的 DNA 甲基化分析确定了可能导致耐药性的基因。
结论
MEK 抑制剂在雪旺细胞瘤模型中表现出抗肿瘤功效的差异，可能出现曲美替尼耐药性。结果支持进一步研究 MEK 抑制剂与其他针对 NF2 雪旺细胞瘤的靶向药物联合使用。
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