The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma.
The Synergistic Anti-Tumor Activity of EZH2 Inhibitor SHR2554 and HDAC Inhibitor Chidamide through ORC1 Reduction of DNA Replication Process in Diffuse Large B Cell Lymphoma.
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EZH2 抑制剂 SHR2554 和 HDAC 抑制剂西达本胺通过 ORC1 减少弥漫性大 B 细胞淋巴瘤 DNA 复制过程的协同抗肿瘤活性
DOI：
10.3390/cancers13174249
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发表时间：
2021-08-24
期刊：
影响因子：
5.2
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Wang X;Wang D;Ding N;Mi L;Yu H;Wu M;Feng F;Hu L;Zhang Y;Zhong C;Ye Y;Li J;Fang W;Shi Y;Deng L;Ying Z;Song Y;Zhu J
EZH 2靶向药物在EZH 2突变型B细胞淋巴瘤患者中显示出显著的治疗效果。在这项研究中，我们证明了EZH 2抑制剂SHR 2554和HDAC抑制剂HBI 8000的组合在EZH 2野生型和突变B细胞淋巴瘤中发挥协同抗增殖活性。更重要的是，基因表达谱分析显示，同时使用这些药物治疗导致DNA复制起始蛋白ORC 1的显著抑制，这可能有助于联合策略的巨大功效。EZH 2抑制剂和HDAC抑制剂的组合可以为EZH 2野生型和突变型B细胞淋巴瘤患者提供潜在的治疗性治疗。摘要背景：EZH 2过表达或体细胞杂合突变诱导的H3 K27 me 3上调与淋巴瘤发生有关。已经证明，几种EZH 2靶向药物在EZH 2突变型B细胞淋巴瘤患者中具有显著的治疗效果。在这里，我们提出了一种新的高选择性EZH 2抑制剂SHR 2554和可能的联合策略在弥漫性大B细胞淋巴瘤（DLBCL）。方法：采用CellTiter-Glo荧光法和流式细胞仪检测细胞增殖、细胞周期和凋亡情况。Western Blot检测相关蛋白的表达。通过RNA-Seq分析组合处理后的基因表达谱。最后，使用CDX和PDX模型来评估组合治疗的体内协同抗肿瘤作用。结果：新型EZH 2抑制剂SHR 2554可抑制EZH 2突变DLBCL细胞的增殖，并诱导细胞发生G1期阻滞。EZH 2抑制剂SHR 2554与组蛋白脱乙酰酶（HDAC）抑制剂西达米特（下文称为HBI 8000）的组合在体外和体内发挥协同抗增殖活性。基因表达谱分析显示，在联合治疗的DNA复制过程的显着抑制。结论：SHR 2554是一种有效的、高选择性的EZH 2小分子抑制剂，在体外和体内均能更显著地抑制EZH 2突变型DLBCL。HDAC抑制剂HBI 8000与EZH 2抑制剂SHR 2554的组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患者的潜在治疗模式。
Simple Summary The EZH2-targeted drugs have demonstrated notable therapeutic effects in EZH2 mutant B-cell lymphoma patients. In this study, we demonstrated that the combination of EZH2 inhibitor SHR2554 and HDAC inhibitor HBI8000 exert synergistic anti-proliferative activity in both EZH2 wide-type and mutation B-cell lymphoma. More importantly, gene expression profile analysis revealed simultaneous treatment with these agents led to dramatic inhibition of DNA replication initiator protein ORC1, which might contribute to great efficacy of combination strategy. The combination of EZH2 inhibitor and HDAC inhibitor could provide a potential therapeutic treatment for both EZH2 wide-type and mutation B-cell lymphoma patients. Abstract Background: 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). Methods: 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. Results: 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. Conclusions: 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.
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影响因子：
16.6
作者：
Piunti, Andrea;Rossi, Alessandra;Cerutti, Aurora;Albert, Mareike;Jammula, Sriganesh;Scelfo, Andrea;Cedrone, Laura;Fragola, Giulia;Olsson, Linda;Koseki, Haruhiko;Testa, Giuseppe;Casola, Stefano;Helin, Kristian;di Fagagna, Fabrizio d'Adda;Pasini, Diego
通讯作者：
Pasini, Diego
影响因子：
3
作者：
Dong, Mei;Ning, Zhi-Qiang;Feng, Feng-Yi
通讯作者：
Feng, Feng-Yi
影响因子：
6.5
作者：
Marchi, Enrica;Zullo, Kelly M.;O'Connor, Owen A.
通讯作者：
O'Connor, Owen A.
体细胞突变改变生发中心起源的滤泡性和弥漫性大 B 细胞淋巴瘤中的 EZH2 (Tyr641)。
影响因子：
30.8
作者：
Morin, Ryan D.;Johnson, Nathalie A.;Severson, Tesa M.;Mungall, Andrew J.;An, Jianghong;Goya, Rodrigo;Paul, Jessica E.;Boyle, Merrill;Woolcock, Bruce W.;Kuchenbauer, Florian;Yap, Damian;Humphries, R. Keith;Griffith, Obi L.;Shah, Sohrab;Zhu, Henry;Kimbara, Michelle;Shashkin, Pavel;Charlot, Jean F.;Tcherpakov, Marianna;Corbett, Richard;Tam, Angela;Varhol, Richard;Smailus, Duane;Moksa, Michelle;Zhao, Yongjun;Delaney, Allen;Qian, Hong;Birol, Inanc;Schein, Jacqueline;Moore, Richard;Holt, Robert;Horsman, Doug E.;Connors, Joseph M.;Jones, Steven;Aparicio, Samuel;Hirst, Martin;Gascoyne, Randy D.;Marra, Marco A.
通讯作者：
Marra, Marco A.
影响因子：
64.8
作者：
Pasqualucci, Laura;Dominguez-Sola, David;Chiarenza, Annalisa;Fabbri, Giulia;Grunn, Adina;Trifonov, Vladimir;Kasper, Lawryn H.;Lerach, Stephanie;Tang, Hongyan;Ma, Jing;Rossi, Davide;Chadburn, Amy;Murty, Vundavalli V.;Mullighan, Charles G.;Gaidano, Gianluca;Rabadan, Raul;Brindle, Paul K.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo