<br>核糖体蛋白的去甲基化促进 MLN4924 和化疗之间的协同作用，从而引发完整的治疗反应,Cell Reports

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核糖体蛋白的去甲基化促进 MLN4924 和化疗之间的协同作用，从而引发完整的治疗反应
Cell Reports ( IF 7.5 ) Pub Date : 2023-08-07 , DOI: 10.1016/j.celrep.2023.112925
Arthur Aubry ₁ , Joel D Pearson ₂ , Jason Charish ₃ , Tao Yu ₂ , Jeremy M Sivak ₄ , Dimitris P Xirodimas ₅ , Hervé Avet-Loiseau ₆ , Jill Corre ₆ , Philippe P Monnier ₃ , Rod Bremner ₇

Affiliation

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Centre Hospitalo-universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Université de Toulouse, UPS, Unité de Génomique du Myélome, Toulouse, France.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada; Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
CRBM, University Montpellier, CNRS, Montpellier, France.
Centre Hospitalo-universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Université de Toulouse, UPS, Unité de Génomique du Myélome, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM, Toulouse, France.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada; Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada.

neddylation 抑制剂 MLN4924/Pevonedistat 正在进行针对多种癌症的临床试验。功效通常归因于 cullin RING 连接酶 (CRL) 抑制，但非 CRL 靶标的贡献尚不清楚。在这里，CRISPR 筛选将视网膜母细胞瘤中 MLN4924 单一疗法的敏感性映射到经典的 DNA 损伤诱导的 p53/E2F3/BAX 依赖性死亡效应网络，该网络与 Nutlin3a 或 Navitoclax 具有协同作用。在单一疗法耐药细胞中，MLN4924 加上标准护理拓扑替康克服了耐药性，但减少了 DNA 损伤，而是利用核糖体蛋白核仁排出来参与 RPL11/p21/MYCN/E2F3/p53/BAX 协同网络，该网络表现出广泛的交叉规定。引人注目的是，unneddylatable RPL11 替代 MLN4924 来扰乱核仁功能并增强拓扑替康功效。原位肿瘤表现出完全反应，同时保留视觉功能。此外，MLN4924 联合美法仑采用这种不依赖 DNA 损伤的策略来协同杀死多发性骨髓瘤细胞。因此，MLN4924 与标准治疗药物协同作用，解锁跨癌症类型的核仁死亡效应网络，这意味着广泛的治疗相关性。

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更新日期：2023-08-07

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