神经纤维瘤病2型(NF2)是由NF2基因中的遗传性灭活突变引起的肿瘤易感综合征，该基因编码梅林抑制肿瘤基因。患者在神经系统中会出现多种良性肿瘤，包括双侧前庭鞍区肿瘤。标准治疗包括手术和放射治疗，但可能导致听力受损、面神经功能受损和其他并发症。对于NF2患者，单一的激酶抑制剂治疗临床疗效有限，迫切需要更有效的非手术治疗方案。鞘瘤模型细胞经PI3K抑制剂治疗后，通过激活焦点粘附激酶家族作为一条代偿性存活途径。我们使用人类同源正常和梅林缺失的Schwann细胞系对13种临床相关PI3K和FAK抑制剂的组合进行了筛选。最有效的组合是PI3K/mTOR抑制剂omipalisib和SRC/FAK抑制剂dasatinib。在单药剂量低于GI50的情况下，这些单药剂量都能阻断它们的主要靶向蛋白的磷酸化。与任何单一药物相比，该组合在促进G1期细胞周期停滞方面更具优势，并在两周的时间内在一个原位移植模型中使肿瘤生长减少了44%。在六种人类原发性前庭鞍区肿瘤细胞模型中评估了单药和组合药物，结果显示在3种前庭鞍区样本中，该组合优于单药治疗，这与其他分子靶向药物的临床试验观察结果一致，突显了患者间的不同肿瘤变异性。Dasatinib单药表现与该组合相当的结果出现在剩下的三个样本中。预临床验证的组合治疗方案对于NF2患者具有潜在的希望，并值得在临床试验中进一步研究。

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas. Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective non-surgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell cycle arrest and produced a 44% decrease in tumor growth over a two-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary vestibular schwannoma cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.