The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2 . Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT- EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT- EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT- EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1 /BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased B-cell maturation and a greater dependence on B-cell activation signaling. Mol Cancer Ther; 16(11); 2586–97. ©2017 AACR .

中文翻译：

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Tazemetostat对EZH2的抑制导致对DLBCL中B细胞激活信号的依赖性改变

EZH2小分子抑制剂tazemetostat（EPZ-6438）目前正在II期临床试验中评估，用于治疗非霍奇金淋巴瘤（NHL）。我们以前已经证明EZH2抑制剂在NHL的多个临床前模型中显示出抗增殖作用，并且具有野生型（WT）EZH2的淋巴瘤对EZH2的抑制作用始终比对野生型（WT）EZH2的淋巴瘤更为敏感。在这里，我们证明了带有EZH2突变的细胞系显示出细胞毒性反应，而带有WT-EZH2的细胞系显示出了细胞抑制反应，并且在异种移植模型中仅抑制了肿瘤生长而没有退化。先前的研究表明，与tazemetostat和糖皮质激素受体激动剂共同处理可在突变型和野生型背景下产生协同的抗增殖作用，这可能为WT-EZH2模型中EZH2抑制作用的机理提供线索。在弥漫性大B细胞淋巴瘤（DLBCL）的突变背景和WT-EZH2背景中，与tazemetostat联合使用时，发现多种抑制B细胞受体途径的药物（例如依鲁替尼）具有协同作用。B细胞活化与EZH2抑制之间的关系与EZH2在B细胞成熟中的拟议作用一致。为了进一步支持这一点，我们观察到用他zemetostat处理的细胞系显示出B细胞成熟调节剂PRDM1 / BLIMP1的增加，并且基因标记对应于成熟的更高级阶段。这些发现表明，在突变和野生型背景中，EZH2的抑制都会导致B细胞成熟度的提高和对B细胞活化信号转导的更大依赖性。分子癌疗法；16（11）; 2586–97。©2017 AACR。