Sun Yichen, Gao Yan, Chen Jianfeng, Huang Ling, Deng Peng, Chen Jinghong, Chai Kelila Xin Ye, Hong Jing Han, Chan Jason Yongsheng, He Haixia, Wang Yali, Cheah Daryl, Lim Jing Quan, Chia Burton Kuan Hui, Huang Dachuan, Liu Lizhen, Liu Shini, Wang Xiaoxiao, Teng Yan, Pang Diwen, Grigoropoulos Nicholas Francis, Teh Bin Tean, Yu Qiang, Lim Soon Thye, Li Wenyu, Ong Choon Kiat, Huang Huiqiang, Tan Jing
State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Lymphoma Division, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, China.
Cancer Lett. 2021 Sep 2;521:268-280. doi: 10.1016/j.canlet.2021.09.002.
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）频繁出现组蛋白乙酰转移酶CREBBP的失活突变，这凸显了将靶向CREBBP缺陷作为一种治疗策略的吸引力。在本研究中，我们证明了新型组蛋白去乙酰化酶（HDAC）抑制剂西达本胺对治疗一部分复发/难治性DLBCL患者有效，总缓解率（ORR）达到25.0%，完全缓解（CR）率为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，这限制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，这与细胞周期机制的调节有关。对130种靶向细胞周期调节因子的激酶抑制剂进行的联合药物筛选确定，抑制细胞周期中G2/M期转换的极光激酶A（AURKA）抑制剂是协同增强西达本胺对CREBBP功能正常的DLBCL细胞抗肿瘤作用的最佳候选药物。我们的研究表明，CREBBP失活可作为预测西达本胺敏感性的潜在生物标志物，而AURKA抑制剂与西达本胺联合使用是治疗复发/难治性DLBCL的一种新的治疗策略。
