Open Access

ARTICLE

A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma

Qiuyun Luo^*†1, Wentao Pan^*†‡1, Suna Zhou^*†1, Guangfeng Wang^‡, Hanjie Yi^*§, Lin Zhang^*¶, Xianglei Yan^*†, Luping Yuan^*†, Zhenyi Liu^#, Jing Wang^**, Haibo Chen^#, MiaoZhen Qiu^*††, DaJun Yang^*†‡, Jian Sun^*‡‡

* State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
† Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
‡ Suzhou Ascentage Pharma Inc., Jiangsu, P.R. China
§ The Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China
¶ University Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
# Peking University Shenzhen Hospital, Shenzhen, P.R. China
** Guangzhou Red Cross Hospital, Guangzhou, P.R. China
†† Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China
‡‡ Department of Clinical Research, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China

Oncology Research 2020, 28(4), 331-344. https://doi.org/10.3727/096504020X15825405463920

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.

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