2 型神经纤维瘤病 (NF2) 是一种罕见疾病，可导致前庭神经鞘瘤 (VS)、脑膜瘤和室管膜瘤。迄今为止，FDA 还没有批准针对 NF2 的药物治疗。我们之前已经发现，BET 抑制可以选择性地减少 NF2 缺失神经鞘瘤和雪旺细胞的体外生长以及体内肿瘤发生，并分别报道通过克唑替尼抑制粘着斑激酶 1 (FAK1) 在 NF2 缺失中具有抗增殖作用雪旺细胞。目前的研究旨在确定 BET 和 FAK 联合抑制是否可以协同作用并确定作用机制。使用一组正常和 NF2 缺失的施万细胞系和神经鞘瘤细胞系，利用药理学和遗传学方法来表征体外和体内 BET 和 FAK 联合抑制的效果。通过染色质免疫沉淀、ChIP-PCR、蛋白质印迹和功能方法探索了作用机制。我们发现，BET 和 FAK 联合抑制具有协同作用，通过将细胞阻滞在细胞周期的 G1/S 和 G2/M 期，在体外和体内抑制 NF2 缺失神经鞘瘤和雪旺细胞系的增殖。此外，我们通过 BET 抑制下调 FAK1 转录来确定作用机制，从而将 FAK 的抑制作用增强 100 倍。我们的研究结果表明，BET 和 FAK1 的联合靶向可能为治疗 NF2 相关神经鞘瘤提供潜在的治疗选择。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Neurofibromatosis type 2 (NF2) is a rare disorder that causes vestibular schwannomas (VS), meningiomas and ependymomas. To date, there is no FDA approved drug-based treatment for NF2. We have previously identified that BET inhibition can selectively reduce growth of the NF2-null schwannoma and Schwann cells in vitro and tumorigenesis in vivo and, separately, reported that inhibition of Focal Adhesion Kinase 1 (FAK1) via crizotinib has antiproliferative effects in NF2-null Schwann cells. The current study was aimed at determining whether combined BET and FAK inhibition can synergize and to identify the mechanisms of action. A panel of normal and NF2-null Schwann and schwannoma cell lines were used to characterize the effects of combined BET and FAK inhibition in vitro and in vivo using pharmacological and genetic approaches. The mechanism of action was explored by chromatin immunoprecipitation, ChIP-PCR, western blotting, and functional approaches. We find that combined BET and FAK inhibition are synergistic and inhibit the proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo, by arresting cells in the G1/S and G2/M phases of the cell cycle. Further, we identify the mechanism of action through the downregulation of FAK1 transcription by BET inhibition, which potentiates inhibition of FAK by 100-fold. Our findings suggest that combined targeting of BET and FAK1 may offer a potential therapeutic option for the treatment of NF2-related schwannomas.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.