中山大学杨大俊等研究人员合作发现，新型BCL-2/BCL-XL抑制剂APG-1252介导的GSDME切割，增强HER2阳性胃癌中HER2靶向治疗的抗肿瘤疗效。这一研究成果于2024年11月26日在线发表在国际学术期刊《中国药理学报》上。

研究人员发现HER2靶向药物上调了GSDME的表达，而GSDME的过度表达降低了HER2靶向药物的敏感性。研究人员进一步观察发现，BCL-2/BCL-XL抑制剂APG-1252联合拉帕替尼促进了GSDME介导的焦亡，并在体内外均表现出显著的抗肿瘤活性。

机制研究表明，APG-1252与拉帕替尼联合通过激活半胱天冬酶依赖的途径并阻断磷酸化AKT/GSK-3β/MCL-1信号通路，协同诱导了HER2阳性胃癌中GSDME介导的焦亡。

这些数据表明，拉帕替尼与APG-1252的联合通过诱导半胱天冬酶-3/GSDME介导的凋亡和焦亡，对HER2阳性胃癌具有协同的抗肿瘤作用。

研究人员表示，HER2阳性胃癌预后较差，耐药发生率高，且耐药患者缺乏有效的治疗方法。亟需探索HER2阳性胃癌中HER2靶向治疗耐药的机制，并识别有效的策略以逆转耐药性。

附：英文原文

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

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

Issue&Volume: 2024-11-26

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.

DOI: 10.1038/s41401-024-01414-5

Source: https://www.nature.com/articles/s41401-024-01414-5