zeste同源物2(EZH2)和Bruton酪氨酸激酶(BTK)的增强子都是血液系统恶性肿瘤发生发展的关键因素。临床研究已经证明了各种EZH2抑制剂的潜力,靶向EZH2的甲基转移酶活性,用于治疗淋巴瘤。然而,尽管它们能够有效降低H3K27me3水平,这些抑制剂在阻断淋巴瘤细胞增殖方面显示出有限的功效。为了克服这一挑战,我们利用选择性EZH2降解剂MS1943采用疏水标记方法。在这项研究中,我们研究了两种药物的抑制作用,FDA批准的EZH2抑制剂Tazemetostat,目前正在进行临床试验,和新的药物MS1943,在伯基特淋巴瘤。此外,我们评估了这些药物与BTK抑制剂依鲁替尼联合使用的潜在协同作用.在这项研究中,我们评估了MS1943和Ibrutinib联合治疗对三种Burkitt淋巴瘤细胞系增殖的影响,即RPMI1788,拉莫斯,还有Daudi细胞.我们的结果表明,与Tazemetostat和Ibrutinib的组合相比,MS1943和Ibrutinib的组合在更大程度上显著抑制了细胞增殖。此外,我们研究了潜在的作用机制,发现MS1943和依鲁替尼的联合治疗导致miR29B介导的p53上调的凋亡调节剂PUMA,巴克斯,裂开的PARP,并在Burkitt淋巴瘤细胞中裂解caspase-3。这些发现凸显了这种创新治疗策略作为传统EZH2抑制剂替代品的潜力。为改善伯基特淋巴瘤的治疗结果提供了有希望的前景。
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.