@article{APS11239,
author = {Qiu-yun Luo and Jing Yang and Tian Di and Zeng-fei Xia and Lin Zhang and Wen-tao Pan and Shan Shi and Li-qiong Yang and Jian Sun and Miao-zhen Qiu and Da-jun Yang},
title = {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},
journal = {Acta Pharmacologica Sinica},
volume = {46},
number = {4},
year = {2025},
keywords = {},
abstract = {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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11239}
}