Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

2 型神经纤维瘤病 (NF2) 相关神经鞘瘤病是一种遗传性疾病，可导致多种类型神经系统肿瘤的发生。原发性和诊断性肿瘤类型是双侧前庭神经鞘瘤。 NF2 没有治愈方法或药物治疗。推荐的治疗方法包括手术切除和放射治疗，这两种方法都会使患者出现严重的神经功能缺损或增加未来患恶性肿瘤的风险。我们之前的试点高通量药物筛选结果基于小鼠 merlin 缺陷型雪旺细胞 (MD-SC) 活力的丧失，确定磷酸肌醇 3-激酶 (PI3K) 抑制剂是强有力的候选药物。在这里，我们使用新型人类神经鞘瘤模型细胞进行组合药物筛选。由于细胞活力测定中的高度协同作用，我们确定 I 类 PI3K 抑制剂 pictilisib 和 p21 激活激酶 (PAK) 抑制剂 PF-3758309 为最佳组合。单一疗法和联合疗法均显着降低了原位同种异体移植小鼠模型中小鼠 MD-SC 的生长。该抑制剂组合促进了小鼠 merlin 缺陷雪旺 (MD-SC) 细胞的细胞周期停滞和细胞凋亡，以及人类 MD-SC 的细胞周期停滞。本研究将 PI3K 和 PAK 通路确定为联合药物治疗 NF2 相关神经鞘瘤病的潜在靶点。