核糖体蛋白去泛素化促进 MLN4924 与化疗的协同作用，从而产生完全的治疗反应。

Deneddylation of ribosomal proteins promotes synergy between MLN4924 and chemotherapy to elicit complete therapeutic responses.

机构信息

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.

出版信息

Cell Rep. 2023 Aug 29;42(8):112925. doi: 10.1016/j.celrep.2023.112925. Epub 2023 Aug 7.

DOI:10.1016/j.celrep.2023.112925

PMID:37552601

Abstract

The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but the contribution of non-CRL targets is unknown. Here, CRISPR screens map MLN4924-monotherapy sensitivity in retinoblastoma to a classic DNA damage-induced p53/E2F3/BAX-dependent death effector network, which synergizes with Nutlin3a or Navitoclax. In monotherapy-resistant cells, MLN4924 plus standard-of-care topotecan overcomes resistance, but reduces DNA damage, instead harnessing ribosomal protein nucleolar-expulsion to engage an RPL11/p21/MYCN/E2F3/p53/BAX synergy network that exhibits extensive cross-regulation. Strikingly, unneddylatable RPL11 substitutes for MLN4924 to perturb nucleolar function and enhance topotecan efficacy. Orthotopic tumors exhibit complete responses while preserving visual function. Moreover, MLN4924 plus melphalan deploy this DNA damage-independent strategy to synergistically kill multiple myeloma cells. Thus, MLN4924 synergizes with standard-of-care drugs to unlock a nucleolar death effector network across cancer types implying broad therapeutic relevance.

摘要

NEDD8 激活酶抑制剂 MLN4924/pevonedistat 正在多种癌症的临床试验中进行研究。其疗效通常归因于 Cullin RING 连接酶（CRL）抑制，但非 CRL 靶点的贡献尚不清楚。在这里，CRISPR 筛选将 MLN4924 单药治疗敏感性映射到经典的 DNA 损伤诱导的 p53/E2F3/BAX 依赖性死亡效应器网络，该网络与 Nutlin3a 或 Navitoclax 协同作用。在单药耐药细胞中，MLN4924 联合标准护理拓扑替康克服耐药性，但降低 DNA 损伤，而是利用核糖体蛋白核仁逐出作用来参与 RPL11/p21/MYCN/E2F3/p53/BAX 协同网络，该网络表现出广泛的交叉调节。引人注目的是，不可 NEDDYLATE 的 RPL11 替代 MLN4924 扰乱核仁功能并增强拓扑替康的疗效。原位肿瘤表现出完全反应，同时保留视觉功能。此外，MLN4924 联合美法仑利用这种 DNA 损伤非依赖性策略协同杀死多发性骨髓瘤细胞。因此，MLN4924 与标准护理药物协同作用，在多种癌症类型中解锁核仁死亡效应器网络，暗示着广泛的治疗相关性。