Diffuse large B-cell lymphoma (DLBCL) exhibits frequent inactivating mutations of the histone acetyltransferase CREBBP, highlighting the attractiveness of targeting CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor, as most patients exhibit resistance, hampering the clinical utility of the drug. Functional in vitro and in vivo studies have shown that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulation of the cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibit the G2/M transition during the cell cycle, as top candidates that synergistically enhanced the antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrates that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while combination of an AURKA inhibitor and chidamide is a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.

弥漫性大 B 细胞淋巴瘤 (DLBCL) 表现出频繁的组蛋白乙酰转移酶CREBBP失活突变，凸显了针对CREBBP缺陷作为治疗策略的吸引力。在这项研究中，我们证明西达本胺是一种新型组蛋白脱乙酰酶 (HDAC) 抑制剂，可有效治疗复发/难治性 DLBCL 患者亚组，实现 25.0% 的总体缓解率 (ORR) 和完全缓解 (CR) 率15.0%。然而，西达本胺的临床反应仍然较差，因为大多数患者表现出耐药性，从而阻碍了该药物的临床应用。体外和体内功能研究表明， CREBBP功能丧失与西达本胺敏感性相关，而西达本胺敏感性与细胞周期机制的调节有关。对 130 种针对细胞周期调节因子的激酶抑制剂进行的组合药物筛选确定了 AURKA 抑制剂，该抑制剂抑制细胞周期中的 G2/M 转变，是协同增强西达本胺在CREBBP熟练的 DLBCL 细胞中的抗肿瘤作用的最佳候选药物。我们的研究表明， CREBBP失活可以作为预测西达本胺敏感性的潜在生物标志物，而 AURKA 抑制剂和西达本胺的组合是治疗复发/难治性 DLBCL 的一种新型治疗策略。