The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations
The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations
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CREB 结合蛋白抑制剂 ICG-001：NF2 突变散发性脑膜瘤的一种有前景的治疗策略
DOI：
10.1093/noajnl/vdz055
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Gong, Ye
中科院分区：
文献类型：
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作者：
Deng, Jiaojiao;Hua, Lingyang;Gong, Ye
摘要背景神经纤维蛋白2基因突变的脑膜瘤（NF 2突变型脑膜瘤）约占散发性脑膜瘤的40%。然而，仍然没有有效的药物治疗这种疾病。方法采用免疫组化方法检测346例脑膜瘤患者中Merlin蛋白的表达。使用脑膜瘤细胞系IOMM-Lee（NF 2野生型）和CH 157-MN（NF 2缺陷型）测试覆盖广泛范围的脑膜瘤相关靶标的20种试剂文库。在体外和患者来源的异种移植物（PDX）模型中进一步表征了所鉴定的化合物ICG-001在NF 2突变型脑膜瘤中的治疗效果和生物学机制。结果在一个大的患者系列中，Merlin低表达与脑膜瘤增殖和不良临床结局相关。ICG-001是一种cAMP反应元件结合（CREB）结合蛋白（CBP）抑制剂，可选择性抑制Merlin低表达细胞的肿瘤生长。此外，ICG-001主要通过强烈诱导G1细胞周期停滞介导CH 157-MN和IOMM-Lee生长抑制。单独用ICG-001治疗也显著降低了小鼠中NF 2突变异种移植物的生长。我们还提供了进一步的证据，ICG-001至少部分地通过减弱FOXM 1介导的Wnt/β-catenin信号传导来抑制NF 2突变型脑膜瘤细胞的增殖。结论本研究强调了配体介导的Wnt/β-catenin信号转导及其在NF 2突变型脑膜瘤中的药物效力的重要性。
Abstract Background Meningiomas with Neurofibromin 2 gene mutations (NF2-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease. Methods Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort (n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee (NF2 wildtype) and CH157-MN (NF2 deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in NF2-mutant meningiomas were further characterized in vitro and in patient-derived xenograft (PDX) models. Results Low Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of NF2-mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2-mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling. Conclusions This study highlights the importance of ligand-mediated Wnt/β-catenin signaling as well as its drugable potency in NF2-mutant meningioma.