Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR .

中文翻译：

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c-Met和Src抑制剂的联合治疗诱导Caspase依赖的Merlin缺陷雪旺细胞凋亡并抑制雪旺细胞的生长。

2型神经纤维瘤病（NF2）是由NF2基因编码的Merlin肿瘤抑制因子失活引起的神经系统肿瘤疾病。双侧前庭神经鞘瘤是NF2的诊断标志。NF2相关肿瘤的主流治疗选择仅限于手术和放疗。然而，靶向分子疗法的标签外使用正变得越来越普遍。在这里，我们研究了靶向两种在NF2相关的神经鞘瘤中激活的激酶的药物，即c-Met和Src。我们证明了用c-Met抑制剂Cabozantinib或Src激酶抑制剂dasatinib和saracatinib处理的梅林缺陷小鼠雪旺细胞（MD-MSC）经历了G1细胞周期停滞。但是，当用卡博替尼和萨拉卡替尼联合治疗MD-MSC时，它们表现出caspase依赖性凋亡。组合疗法还显着降低了原位同种异体移植小鼠模型中MD-MSC的生长，其溶出度超过载体的80％。此外，与媒介物对照相比，当用卡博替尼和萨拉卡替尼治疗时，具有NF2突变的人前庭神经鞘瘤细胞的细胞活力降低了40％。这项研究表明，同时抑制MD-MSC中的c-Met和Src信号传导会触发细胞凋亡，并揭示了可用于开发NF2治疗的易受攻击的途径。分子癌疗法；16（11）; 2387–98。©2017 AACR。与媒介物对照相比，用卡博替尼和萨拉卡替尼治疗时，具有NF2突变的人前庭神经鞘瘤细胞的细胞活力下降了40％。这项研究表明，同时抑制MD-MSC中的c-Met和Src信号传导会触发细胞凋亡，并揭示了可用于开发NF2治疗的易受攻击的途径。分子癌疗法；16（11）; 2387–98。©2017 AACR。与媒介物对照相比，用卡博替尼和萨拉卡替尼治疗时，具有NF2突变的人前庭神经鞘瘤细胞的细胞活力降低了40％。这项研究表明，同时抑制MD-MSC中的c-Met和Src信号传导会触发细胞凋亡，并揭示了可用于开发NF2治疗的易受攻击的途径。分子癌疗法；16（11）; 2387–98。©2017 AACR。