Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors
Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors
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DOI：
10.1016/j.celrep.2021.109568
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发表时间：
2021-08-24
期刊：
影响因子：
8.8
通讯作者：
Drost, Jarno
中科院分区：
文献类型：
--
作者：
Calandrini, Camilla;van Hooff, Sander R.;Drost, Jarno
恶性横纹肌样肿瘤（MRTs）是最具侵袭性的儿童恶性肿瘤之一。没有有效的治疗选择，因此预后很差。先前的研究表明，肿瘤类器官捕获了患者肿瘤的异质性，并可用于预测患者对治疗的反应。在这里，我们对患者来源的正常和肿瘤类器官进行药物筛选，以确定mrt特异性治疗脆弱性。我们确定类化化抑制剂MLN4924是一种潜在的治疗剂。在机制上，我们发现MRT类器官和组织中的类木化修饰增加，并表明MLN4924通过上调未折叠蛋白反应诱导细胞毒性反应。最后，我们在MRT PDX小鼠模型中证明了体内疗效，其中单药MLN4924治疗显着延长了生存期。我们的研究表明，类器官可以用来寻找选择性靶向肿瘤细胞的药物，同时不伤害健康细胞，并提出了类化抑制作为MRT的治疗策略。
Malignant rhabdoid tumors (MRTs) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is, therefore, dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient response to therapy. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate in vivo efficacy in an MRT PDX mouse model, in which single-agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as a therapeutic strategy in MRT.