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