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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

Qiu-yun Luo1,2, Jing Yang1,3, Tian Di1, Zeng-fei Xia1, Lin Zhang1,4, Wen-tao Pan1,5, Shan Shi1, Li-qiong Yang1, Jian Sun2, Miao-zhen Qiu1,3, Da-jun Yang1,5
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
Correspondence to: Jian Sun: sjian@mail.sysu.edu.cn, Miao-zhen Qiu: qiumzh@sysucc.org.cn, Da-jun Yang: yangdj@sysucc.org.cn,
DOI: 10.1038/s41401-024-01414-5
Received: 21 June 2024
Accepted: 20 October 2024
Advance online: 26 November 2024

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.
Keywords: HER2-positive gastric cancer; GSDME; pyroptosis; APG-1252

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