Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.
Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.
复制标题
蛋白酶体途径抑制作为 NF2 相关脑膜瘤和神经鞘瘤的潜在疗法。
DOI：
10.1093/neuonc/noad037
复制
发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Ramesh,Vijaya
中科院分区：
文献类型：
--
作者：
Bhattacharyya,Srirupa;Oblinger,JanetL;Beauchamp,RobertaL;Yin,Zhenzhen;Erdin,Serkan;Koundinya,Priya;Ware,AnnaD;Ferrer,Marc;Jordan,JustinT;Plotkin,ScottR;Xu,Lei;Chang,Long-Sheng;Ramesh,Vijaya
背景神经纤维瘤病 2 (NF2) 是一种由 NF2 肿瘤抑制基因双等位基因失活引起的遗传性疾病。 NF2相关肿瘤，包括神经鞘瘤和脑膜瘤，对化疗有抵抗力，尽管进行了手术和/或放疗，通常仍会复发，并且通常对信号转导通路抑制剂表现出细胞抑制反应，这凸显了改进细胞毒性疗法的必要性。 方法利用我们之前在 NF2 临床前模型中进行的高通量药物筛选的数据，我们鉴定了一类针对泛素-蛋白酶体通路 (UPP) 的化合物，并使用候选化合物进行了研究UPP 抑制剂、ixazomib/MLN9708、pevonedistat/MLN4924 和 TAK-243/MLN7243。采用人类原代和永生化脑膜瘤 (MN) 细胞系、CRISPR 修饰的雪旺细胞 (SC) 和小鼠 Nf2−/−SC，我们进行了剂量反应测试、基于流式细胞术的膜联蛋白 V 和细胞周期分析以及 RNA 测序，以确定潜在的细胞凋亡机制。还在原位 NF2 缺陷型脑膜瘤和神经鞘瘤肿瘤模型中评估了体内功效。三种 UPP 抑制剂的结果显示，ixazomib 或 TAK-243 可有效降低细胞活力并诱导细胞凋亡，但 pevonedistat 则不然。体外分析显示，ixazomib 或 TAK-243 下调 c-KIT 和 PDGFRα 以及 E3 泛素连接酶 SKP2 的表达，同时上调与内质网应激介导的未折叠蛋白反应激活相关的基因(UPR)。小鼠模型的体内治疗显示肿瘤生长延迟，表明具有治疗潜力。结论这项研究证明了蛋白酶体途径抑制剂在脑膜瘤和神经鞘瘤临床前模型中的功效，并为使用这些药物作为 NF2 患者的有前途的新型治疗策略奠定了基础。
BackgroundNeurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of theNF2tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies.MethodsLeveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin–proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouseNf2−/−SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis.In vivoefficacy was also assessed in orthotopicNF2-deficient meningioma and schwannoma tumor models.ResultsTesting of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat.In vitroanalyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR).In vivotreatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential.ConclusionsThis study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.