期刊
CANCER LETTERS
卷 521, 期 -, 页码 268-280出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.09.002
关键词
DLBCL; CREBBP; Chidamide; Resistance; Cell cycle
类别
资金
- National Natural Science Foundation of China [81970176, 81972596, 81772963]
- Guangdong Innovative and Entrepreneurial Research Team Program [2016ZT06S638]
- Natural Science Foundation of Guangdong Province [2021A1515011131]
- Sci Tech Project Foundation of Guangzhou City [201707020039]
- National Science & Technology Major Project [2017ZX09304021]
- Singapore Ministry of Health's National Med-ical Research Council [NMRC-ORIRG16nov090, NMRC-OFLCG18-May0028]
- Tanoto Foundation
- Ling Foundation
The study demonstrates that DLBCL patients with CREBBP deficiency respond well to the HDAC inhibitor chidamide, especially when combined with an AURKA inhibitor.
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.
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