Jeong Yurim, Kim Se Been, Yang Chae-Eun, Yu Min Seo, Choi Wan-Su, Jeon Youngwoo, Lim Jung-Yeon
Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea.
Department of Digital Anti-aging Health Care, Inje University, Gimhae, Republic of Korea.
Front Oncol. 2023 Sep 11;13:1252658. doi: 10.3389/fonc.2023.1252658. eCollection 2023.
Enhancer of zeste homolog 2 (EZH2) and Bruton's tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt's lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt's lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt's lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt's lymphoma.
zeste 同源物 2 增强子（EZH2）和布鲁顿酪氨酸激酶（BTK）都是参与血液系统恶性肿瘤发生和发展的关键因素。临床研究已经证明了多种靶向 EZH2 甲基转移酶活性的 EZH2 抑制剂在治疗淋巴瘤方面的潜力。然而，尽管这些抑制剂能够有效降低 H3K27me3 水平，但在阻断淋巴瘤细胞增殖方面显示出有限的疗效。为了克服这一挑战，我们采用了一种利用选择性 EZH2 降解剂 MS1943 的疏水标记方法。在本研究中，我们研究了两种药物——目前正在进行临床试验的 FDA 批准的 EZH2 抑制剂他泽司他以及新型药物 MS1943——对伯基特淋巴瘤的抑制作用。此外，我们评估了将这些药物与 BTK 抑制剂伊布替尼联合使用的潜在协同效应。在本研究中，我们评估了 MS1943 和伊布替尼联合治疗对三种伯基特淋巴瘤细胞系，即 RPMI1788、Ramos 和 Daudi 细胞增殖的影响。我们的结果表明，与他泽司他和伊布替尼联合使用相比，MS1943 和伊布替尼联合使用能更显著地抑制细胞增殖。此外，我们研究了其潜在的作用机制，发现 MS1943 和伊布替尼联合治疗导致伯基特淋巴瘤细胞中 miR29B 介导的 p53 上调凋亡调节因子 PUMA、BAX、裂解的 PARP 和裂解的半胱天冬酶 -3 上调。这些发现突出了这种创新治疗策略作为传统 EZH2 抑制剂替代方案的潜力，为改善伯基特淋巴瘤的治疗结果提供了有希望的前景。
