Wang Xing, Wang Dedao, Ding Ning, Mi Lan, Yu Hui, Wu Meng, Feng Feier, Hu Luni, Zhang Yime, Zhong Chao, Ye Yingying, Li Jiao, Fang Wei, Shi Yunfei, Deng Lijuan, Ying Zhitao, Song Yuqin, Zhu Jun
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.
Institute of Systems Biomedicine, Department of Immunology, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
Cancers (Basel). 2021 Aug 24;13(17):4249. doi: 10.3390/cancers13174249.
Upregulation of H3K27me3 induced by EZH2 overexpression or somatic heterozygous mutations were implicated in lymphomagenesis. It has been demonstrated that several EZH2-target agents have notable therapeutic effects in EZH2-mutant B-cell lymphoma patients. Here we present a novel highly selective EZH2 inhibitor SHR2554 and possible combination strategy in diffuse large B-cell lymphoma (DLBCL).
Cell proliferation, cell cycle and apoptosis were analyzed by CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. Western Blot was used to detect the expression of related proteins. The gene expression profiling post combination treatment was analyzed by RNA-Seq. Finally, CDX and PDX models were used to evaluate the synergistic anti-tumor effects of the combination treatment in vivo.
The novel EZH2 inhibitor SHR2554 inhibited proliferation and induced G1 phase arrest in EZH2-mutant DLBCL cell lines. The combination of EZH2 inhibitor SHR2554 with histone deacetylase (HDAC) inhibitor chidamide (hereafter referred to as HBI8000) exerted synergistic anti-proliferative activity in vitro and in vivo. Gene expression profile analysis revealed dramatic inhibition of the DNA replication process in combined treatment.
SHR2554, a potent, highly selective small molecule inhibitor of EZH2, inhibited EZH2-mutant DLBCL more significantly in vitro and in vivo. The combination of HDAC inhibitor HBI8000 with EZH2 inhibitor SHR2554 exhibited dramatic anti-tumor activity in both mutant and wild-type DLBCL, which may become a potential therapeutic modality for the treatment of DLBCL patients.
EZH2过表达或体细胞杂合突变诱导的H3K27me3上调与淋巴瘤发生有关。已经证明，几种EZH2靶向药物对EZH2突变的B细胞淋巴瘤患者具有显著的治疗效果。在此，我们介绍一种新型的高选择性EZH2抑制剂SHR2554以及弥漫性大B细胞淋巴瘤（DLBCL）中可能的联合治疗策略。
通过CellTiter-Glo发光细胞活力测定法和流式细胞术分析细胞增殖、细胞周期和凋亡。使用蛋白质免疫印迹法检测相关蛋白的表达。通过RNA测序分析联合治疗后的基因表达谱。最后，使用CDX和PDX模型评估联合治疗在体内的协同抗肿瘤作用。
新型EZH2抑制剂SHR2554抑制EZH2突变的DLBCL细胞系的增殖并诱导G1期阻滞。EZH2抑制剂SHR2554与组蛋白脱乙酰酶（HDAC）抑制剂西达本胺（以下简称HBI8000）联合在体外和体内均发挥协同抗增殖活性。基因表达谱分析显示联合治疗对DNA复制过程有显著抑制作用。
SHR2554是一种强效、高选择性的EZH2小分子抑制剂，在体外和体内对EZH2突变的DLBCL有更显著的抑制作用。HDAC抑制剂HBI8000与EZH2抑制剂SHR2554联合在突变型和野生型DLBCL中均表现出显著的抗肿瘤活性，这可能成为治疗DLBCL患者的一种潜在治疗方式。
