The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradatio, State Key Laboratory of Respiratory Disease; Affiliated Cancer Hospital of Guangzhou Medical University; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou P.R. China.
Department of Obstetrics and Gynaecology, Dongguan Affiliated Hospital, Southern Medical University, Dongguan, P.R. China.
Cancer Biol Ther. 2022 Dec 31;23(1):319-327. doi: 10.1080/15384047.2022.2055421.
Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory or relapse to standard chemotherapy, and most of them are activated B cell-like DLBCLs (ABC-DLBCL) and germinal center B cell-like DLBCLs (GCB-DLBCL). SNS-032, a novel and selective CDK7/9 inhibitor, that the first phase clinical trials approved by US FDA for cancer treatment have been completed. In this study, we investigated the anti-tumor effect of SNS-032 in ABC- and GCB-DLBCL subtypes. We report that SNS-032 induced growth inhibition and cell apoptosis in both DLBCL cells in vitro, and inhibited the growth of both DLBCL xenografts in nude mice. Mechanistically, SNS-032 inhibited RNA polymerase II, which led to transcriptional-dependent suppression of NF-κB signaling pathway and its downstream targets involved in cell survival; SNS-032 also downregulates BCL-2 and c-MYC in both mRNA and protein levels. Significantly, these findings provide pre-clinical evidence for application of targeting the CDK7/9 in DLBCL.
大约 40%弥漫性大 B 细胞淋巴瘤（DLBCL）患者对标准化疗具有耐药性或复发，其中大多数为激活 B 细胞样 DLBCL（ABC-DLBCL）和生发中心 B 细胞样 DLBCL（GCB-DLBCL）。SNS-032 是一种新型、选择性细胞周期蛋白依赖性激酶 7/9（CDK7/9）抑制剂，已被美国 FDA 批准用于癌症治疗的 I 期临床试验。在这项研究中，我们研究了 SNS-032 在 ABC 和 GCB-DLBCL 亚型中的抗肿瘤作用。我们报告 SNS-032 在体外均能抑制 DLBCL 细胞的生长和诱导细胞凋亡，并能抑制裸鼠中两种 DLBCL 异种移植物的生长。从机制上讲，SNS-032 抑制 RNA 聚合酶 II，导致转录依赖性抑制 NF-κB 信号通路及其下游参与细胞存活的靶标；SNS-032 还下调了 BCL-2 和 c-MYC 的 mRNA 和蛋白水平。重要的是，这些发现为靶向 CDK7/9 在 DLBCL 中的应用提供了临床前证据。
