The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer  

作　　者：Qiu-yun Luo Jing Yang Tian Di Zeng-fei Xia Lin Zhang Wen-tao Pan Shan Shi Li-qiong Yang Jian Sun Miao-zhen Qiu Da-jun Yang 

机构地区：[1]State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou,510060,China [2]Department of Clinical Research Center,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou,510060,China [3]Department of Medical Oncology,Sun Yat-sen University Cancer Center,Guangzhou,510060,China [4]Department of Clinical Laboratory,Sun Yat-sen University Cancer Center,Guangzhou,510060,China [5]Ascentage Pharma(Suzhou)Co,Ltd,Suzhou,215000,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1082-1096,共15页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(NSFC:82172748 and 82073377);the Guangdong Basic and Applied Basic Research Foundation(2024B1515020120 and 2023A1515110567);the Medical Scientific Research Foundation of Guangdong Province(A2024171).

摘　　要：HER2-positive gastric cancer has a poor prognosis,with a high incidence of drug resistance and a lack of effective treatments for drug-resistant patients.The exploration of the mechanism of resistance to HER2-targeted therapy in HER2-positive gastric cancer and the identification of effective strategies to reverse it are urgently needed.In this study,we found that HER2-targeted agents upregulated the expression of GSDME and that the overexpression of GSDME attenuated the sensitivity of HER2-targeted agents.Furthermore,we observed that the BCL-2/BCL-XL inhibitor APG-1252 plus lapatinib promoted GSDME-mediated pyroptosis and exhibited remarkable antitumor activity both in vitro and in vivo.Mechanistically,APG-1252 combined with lapatinib synergistically induced GSDME-mediated pyroptosis in HER2-positive gastric cancer by activating caspase-dependent pathways and blocking the phospho-AKT/GSK-3β/MCL-1 signaling pathway.Our data indicated that the combination of lapatinib and APG-1252 had a synergistic antitumor effect on HER2-positive gastric cancer through the induction of caspase-3/GSDME-mediated apoptosis and pyroptosis.

关 键 词：HER2-positive gastric cancer GSDME PYROPTOSIS APG-1252 

分 类 号：R735.2[医药卫生—肿瘤]