Open AccessA Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma
Author(s) -
Qiuyun Luo,
Wentao Pan,
Suna Zhou,
Guangfeng Wang,
Hanjie Yi,
Lin Zhang,
Xin Yan,
Luping Yuan,
Zhenyi Liu,
Jing Wang,
Haibo Chen,
Miaozhen Qiu,
Dajun Yang,
Jian Sun
Publication year - 2020
Publication title -
oncology research
Language(s) - English
Resource type - Journals
eISSN - 1555-3906
pISSN - 0965-0407
DOI - 10.3727/096504020x15825405463920
Subject(s) - ibrutinib , bruton's tyrosine kinase , cancer research , lymphoma , diffuse large b cell lymphoma , protein kinase b , tyrosine kinase , chronic lymphocytic leukemia , myeloid leukemia , apoptosis , biology , leukemia , medicine , signal transduction , immunology , microbiology and biotechnology , biochemistry
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 Brutons 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 MDM2p53 inhibitors for DLBCL, which deserves further clinical investigation.