文章：

靶向CDK11治疗肾脏横纹肌样瘤

Targeting CDK11 in Rhabdoid Tumor of the Kidney

原文发布日期：14 January 2026

DOI: 10.3390/cancers18020261

类型: Article

开放获取: 是

英文摘要：

Background: Rhabdoid tumor of the kidney (RTK) is a highly aggressive pediatric malignancy characterized by biallelicSMARCB1loss, resulting in aberrant MYC pathway activation and cell cycle regulation. MYC-activated tumors are vulnerable in splicing functions and sensitive to splicing inhibitors. Therefore, in this study, cyclin-dependent kinase 11 (CDK11), which regulates both cell cycle and RNA splicing, was tested as a therapeutic target in RTK. Methods:CDK11A/Bexpression was analyzed using the TARGET-RT database. The therapeutic efficacy of the CDK11 inhibitor OTS964 was evaluated in two RTK cell lines (G401 and JMU-RTK-2) and a JMU-RTK-2 xenograft mouse model. Cytotoxicity, apoptosis, cell cycle, and RNA splicing were examined using the Sulforhodamine B assay, immunoblotting, flow cytometry, and RT-PCR. Results:CDK11B, but notCDK11A, was significantly upregulated in RTK and correlated with the poor survival. OTS964 inhibited RTK cell growth in vitro with the IC50 of 33.1 nM (G401) and 19.3 nM (JMU-RTK-2) and significantly prolonged survival in vivo (median survival: 46.5 vs. 37.0 days,p< 0.01) without marked toxicity. Mechanistically, OTS964 induced G2/M cell cycle arrest and p53 upregulation, disrupted RNA splicing via SF3B1 dephosphorylation, and ultimately led to apoptosis through caspase-3 activation. Conclusions: CDK11 inhibition by OTS964 effectively suppresses RTK growth through cell cycle arrest and RNA splicing inhibition, leading to apoptosis. OTS964 shows potent anti-tumor activity and tolerability, supporting CDK11 as a promising therapeutic target for RTK and relatedSMARCB1-deficient cancers.

摘要翻译： 

背景：肾横纹肌样瘤（RTK）是一种高度恶性的儿童肿瘤，其特征为SMARCB1双等位基因缺失，导致MYC通路异常激活和细胞周期调控紊乱。MYC激活的肿瘤在RNA剪接功能上存在脆弱性，并对剪接抑制剂敏感。因此，本研究探讨了同时调控细胞周期和RNA剪接的细胞周期蛋白依赖性激酶11（CDK11）作为RTK治疗靶点的潜力。方法：利用TARGET-RT数据库分析CDK11A/B表达。在两种RTK细胞系（G401与JMU-RTK-2）及JMU-RTK-2异种移植小鼠模型中评估CDK11抑制剂OTS964的治疗效果。采用磺酰罗丹明B实验、免疫印迹、流式细胞术和RT-PCR检测细胞毒性、凋亡、细胞周期及RNA剪接变化。结果：CDK11B（而非CDK11A）在RTK中显著上调，且与不良预后相关。OTS964在体外抑制RTK细胞生长的IC50为33.1 nM（G401）和19.3 nM（JMU-RTK-2），并在体内显著延长小鼠生存期（中位生存期：46.5天 vs. 37.0天，p<0.01），且未观察到明显毒性。机制上，OTS964通过诱导G2/M期细胞周期阻滞、上调p53表达、介导SF3B1去磷酸化破坏RNA剪接，最终经caspase-3激活导致细胞凋亡。结论：OTS964通过抑制CDK11可有效阻滞细胞周期并抑制RNA剪接，从而诱导凋亡、抑制RTK生长。该药物展现出显著的抗肿瘤活性与耐受性，支持CDK11作为RTK及相关SMARCB1缺失型癌症的潜在治疗靶点。

原文链接：

Targeting CDK11 in Rhabdoid Tumor of the Kidney