@Article{096504020X15825405463920,
AUTHOR = {Qiuyun Luo, Wentao Pan, Suna Zhou,
 Guangfeng Wang, Hanjie Yi, Lin Zhang, 
Xianglei Yan, Luping Yuan, Zhenyi Liu, Jing Wang, Haibo Chen, MiaoZhen Qiu, 
DaJun Yang, Jian Sun},
TITLE = {A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK  or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma},
JOURNAL = {Oncology Research},
VOLUME = {28},
YEAR = {2020},
NUMBER = {4},
PAGES = {331--344},
URL = {http://www.techscience.com/or/v28n4/48517},
ISSN = {1555-3906},
ABSTRACT = {Despite therapeutic advances, the effective treatment for relapsed or refractory diffuse large B-cell lymphoma 
(DLBCL) remains a major clinical challenge. Evasion of apoptosis through upregulating antiapoptotic B-cell 
lymphoma-2 (BCL-2) family members and p53 inactivation, and abnormal activation of B-cell receptor signaling pathway are two important pathogenic factors for DLBCL. In this study, our aim is to explore a rational 
combination of BCL-2 inhibitor plus Bruton’s tyrosine kinase (BTK) blockade or p53 activation for treating 
DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 
effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL 
with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression 
level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of 
BCL-2, APG-2575 showed strong synergic effect with mouse double minute 2 (MDM2)–p53 inhibitor APG-
115 that can achieve potent antitumor effect and markedly prolong survival in animal models. Collectively, our 
data provide an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or 
MDM2–p53 inhibitors for DLBCL, which deserves further clinical investigation.},
DOI = {10.3727/096504020X15825405463920}
}