靶向神经鞘瘤中的Hippo-MAPK串扰：通过双重抑制克服耐药性

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中文摘要

背景： NF2相关神经鞘瘤病患者会发展出称为神经鞘瘤的标志性肿瘤，这些肿瘤可引起麻木、疼痛、听力下降和平衡问题。目前尚无FDA批准的用于神经鞘瘤的药物。放射治疗和手术切除是主要治疗选择，但可能造成神经损伤。神经鞘瘤起源于携带NF2基因突变的施万细胞。NF2功能缺失导致多种已知在神经鞘瘤发生中起作用的信号通路失调，包括Hippo和MAPK通路。我们此前报道，在遗传小鼠模型中Hippo通路失调会导致多个神经鞘瘤的发生，这些肿瘤可重现人类肿瘤；并且在这些小鼠中通过Nf1缺失进一步激活RAS/MAPK通路会增加肿瘤负荷并降低总生存期。结果：在此，我们显示，分别使用泛TEAD抑制剂和MEK抑制剂联合抑制失调的Hippo信号和MAPK激酶信号，在减缓肿瘤生长方面比任一单药更有效。结论：我们的发现为泛TEAD抑制剂联合MEK抑制剂治疗神经鞘瘤的临床测试提供了支持。

英文摘要

Individuals with NF2-related schwannomatosis develop hallmark tumors called schwannomas that can cause numbness, pain, hearing loss, and balance issues. There are currently no FDA-approved drugs for schwannoma. Radiation and surgical removal, which can cause nerve damage, are the mainstay treatment options. Schwannomas arise from Schwann cells harboring mutations in the gene NF2. Functional loss of NF2 results in dysregulation of a number of signaling pathways known to play a role in schwannomagenesis, including the Hippo and MAPK pathways. We previously reported that Hippo pathway dysregulation in a genetic mouse model causes development of multiple schwannomas that recapitulate the human tumors, and that further activation of RAS/MAPK pathway via Nf1 deletion in these mice increased tumor burden and reduced overall survival. Here, we show that combined inhibition of dysregulated Hippo signaling and MAPK kinase signaling using a pan-TEAD inhibitor and a MEK inhibitor, respectively, is more effective at slowing tumor growth than either inhibitor alone. Our findings provide support for clinical testing of a pan-TEAD inhibitor plus a MEK inhibitor combination treatment for schwannoma.