Cyclin-dependent kinase 7/9 inhibitor SNS-032 induces apoptosis in diffuse large B-cell lymphoma cells

• Published in: Cancer biology & therapy 2022-12, Vol.23 (1), p.319-327
• Main Authors: Jiang, Liling, Wen, Chuangyu, Zhou, Huan, Liu, Aochu, Zhang, Haichuan, Chen, Xinmei, Ding, Wa, Liu, Jinbao, Shi, Xianping
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; chemotherapy; cyclin-dependent kinase 7/9; Cyclin-Dependent Kinases; diffuse large B-cell lymphoma; Humans; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Mice; Mice, Nude; Neoplasm Recurrence, Local; Oxazoles; Research Paper; SNS-032; Thiazoles
• ISSN: 1538-4047; 1555-8576
• 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.