A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity

作者：Pan, Wentao; Luo, Qiuyun; Yan, Xianglei; Yuan, Luping; Yi, Hanjie; Zhang, Lin; Li, Baoxia; Zhang, Yuxin; Sun, Jian^*; Qiu, Miao-Zhen^*; Yang, Da-Jun^*

来源：Biochemical Pharmacology, 2018, 154: 127-135.

DOI：10.1016/j.bcp.2018.04.020

• Apoptosis
• Check point inhibitors
• Hepatitis B virus
• Hepatocellular carcinoma
• SMAC-mimetic

Check point inhibitor anti-PDl antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAPl, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG-1387 alone could induce apoptosis of PLC/PRF/ 5 which was HBV positive both in-vitro and in-vivo. Furthermore, we found that APG-1387 significantly up-regulated the expression of calreticulin and HLA-DR in PLC/PRF/5 via activating non-classic NF-kB pathway. Also, compared to vehicle group, APG-1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In-vitro, APG-1387 positively regulated T cells by reducing Treg differentiation and down-regulating PD1 expression in CD4 T cell. Moreover, APG-1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti-PDl antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC.

• 出版日期2018-8
• 单位中山大学; 华南肿瘤学国家重点实验室