MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors
MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors
复制标题
DOI：
10.1172/jci60578
复制
发表时间：
2013-01-01
影响因子：
15.9
通讯作者：
Ratner, Nancy
中科院分区：
文献类型：
--
作者：
Jessen, Walter J.;Miller, Shyra J.;Ratner, Nancy
1型神经纤维瘤病（NF 1）患者发生良性神经纤维瘤和恶性外周神经鞘瘤（MPNST）。这些无法治愈的外周神经肿瘤是由于NF 1肿瘤抑制基因功能的丧失，导致Ras信号过度活跃。活化的Ras控制许多下游效应物，但在NF 1肿瘤中介导过度活化的Ras作用的具体途径尚不清楚。我们对小鼠和人类神经纤维瘤和MPNST进行了跨物种转录组分析，并确定了两个物种中调节Ras/Raf/MEK/ERK信号传导的基因的全局负反馈。尽管如此，ERK激活在小鼠和人类神经纤维瘤和MPNST中持续存在。我们使用了一种高选择性的MEK药理学抑制剂PD 0325901来测试持续的Ras/Raf/MEK/ERK信号传导是否有助于神经纤维瘤病小鼠模型（Nf 1 N（fl/fl）;Dhh-Cre）或NF 1患者MPNST细胞异种移植物中的神经纤维瘤生长。PD 0325901治疗减少了神经纤维瘤和MPNST中的异常增殖细胞，延长了植入人MPNST细胞的小鼠的存活时间，并使超过80%的受试小鼠的神经纤维瘤缩小。我们的数据表明，Ras/ERK信号的失调对于NF 1周围神经肿瘤的生长至关重要，并为在NF 1临床试验中测试MEK抑制剂提供了强有力的理论基础。
Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1N(fl/fl);Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.