PDF(Pubmed)
Abstract：
Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.
摘要：
神经纤维瘤病2型是一种遗传性疾病，导致神经鞘瘤的形成和进行性生长，室管膜瘤,和/或脑膜瘤。NF2基因编码Merlin蛋白,它将细胞皮质元件连接到肌动蛋白细胞骨架，并调节许多关键酶，包括I组p21活化激酶（PAKs），Hippo途径激酶LATS，和mTORC。当Merlin突变或缺失时，PAK1和PAK2直接结合Merlin并传递增殖和存活信号，单独抑制第1组PAK还不足以在体内完全阻止NF2缺陷型脑膜瘤或神经鞘瘤的生长，提示需要第二种途径抑制剂。由于Hippo途径在NF2缺陷细胞中也被激活，最近已经以YAP-TEAD结合抑制剂的形式开发了几种Hippo途径的抑制剂。这些抑制剂防止促增殖和抗凋亡Hippo途径效应物的活化。在这项研究中,我们显示PAK抑制减缓细胞增殖，而TEAD抑制促进凋亡细胞死亡。最后,我们证明了PAK和TEAD抑制剂组合在几种NF2缺陷型神经鞘瘤细胞系中的疗效.
