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

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS BOTH DIRECT AND INDIRECT SUPPRESSION OF MCL1 SYNERGIZES WITH BCLXL INHIBITION IN

PRECLINICAL MODELS OF GASTRIC CANCER Article Open access 12 March 2025 TARGETING THE AUTOPHAGY PROMOTED ANTITUMOR EFFECT OF T-DM1 ON HER2-POSITIVE GASTRIC CANCER Article Open access 17

March 2021 TALETRECTINIB PROMOTES PYROPTOSIS IN COLORECTAL CARCINOMA VIA SRC/AKT/MTOR AXIS INHIBITION Article Open access 24 May 2025 DATA AVAILABILITY The datasets supporting the

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cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis. Cancer Lett. 2021;520:143–59. Article  CAS  PubMed  Google Scholar  Download references FUNDING This study was

supported by the National Natural Science Foundation of China (NSFC: 82172748 and 82073377), the Guangdong Basic and Applied Basic Research Foundation (2024B1515020120 and 2023A1515110567),

and the Medical Scientific Research Foundation of Guangdong Province (A2024171). AUTHOR INFORMATION Author notes * These authors contributed equally: Qiu-yun Luo, Jing Yang, Tian Di,

Zeng-fei Xia AUTHORS AND AFFILIATIONS * State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou,

510060, China Qiu-yun Luo, Jing Yang, Tian Di, Zeng-fei Xia, Lin Zhang, Wen-tao Pan, Shan Shi, Li-qiong Yang, Miao-zhen Qiu & Da-jun Yang * Department of Clinical Research Center, The

Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510060, China Qiu-yun Luo & Jian Sun * Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou,

510060, China Jing Yang & Miao-zhen Qiu * Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China Lin Zhang * Ascentage Pharma (Suzhou) Co, Ltd,

Suzhou, 215000, China Wen-tao Pan & Da-jun Yang Authors * Qiu-yun Luo View author publications You can also search for this author inPubMed Google Scholar * Jing Yang View author

publications You can also search for this author inPubMed Google Scholar * Tian Di View author publications You can also search for this author inPubMed Google Scholar * Zeng-fei Xia View

author publications You can also search for this author inPubMed Google Scholar * Lin Zhang View author publications You can also search for this author inPubMed Google Scholar * Wen-tao Pan

View author publications You can also search for this author inPubMed Google Scholar * Shan Shi View author publications You can also search for this author inPubMed Google Scholar *

Li-qiong Yang View author publications You can also search for this author inPubMed Google Scholar * Jian Sun View author publications You can also search for this author inPubMed Google

Scholar * Miao-zhen Qiu View author publications You can also search for this author inPubMed Google Scholar * Da-jun Yang View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS DJY, MZQ, and JS conceived and designed the experiments of this study. QYL and JY conducted the in vitro experiments and drafted the manuscript. TD and

ZFX performed the animal experiments and assisted with manuscript revisions. LZ and WTP analyzed the data and prepared the statistical figures. SS and LQY contributed to the materials and

analysis tool used in the study and helped with manuscript revision. CORRESPONDING AUTHORS Correspondence to Jian Sun, Miao-zhen Qiu or Da-jun Yang. ETHICS DECLARATIONS COMPETING INTERESTS

DJY holds ownership interests, including patents, in Ascentage Pharma Group Corp. Limited. WTP is an employee of Ascentage Pharma Group Corp. Limited. The remaining authors have no potential

conflicts of interest to disclose. ETHICS APPROVAL AND CONSENT TO PARTICIPATE The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Review

Committee of Sun Yat-sen University Cancer Center (B2022-633-01). Informed written consent was obtained from all participants. The in vivo animal experiments were approved by the animal

experimentation ethics committee and carried out under the guidance of the Sun Yat-Sen University Committee for the Use and Care of Laboratory Animals (Approval number: L102012022110I).

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agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Luo, Qy., Yang, J., Di, T. _et al._ 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. _Acta Pharmacol Sin_ 46, 1082–1096 (2025). https://doi.org/10.1038/s41401-024-01414-5

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * HER2-positive gastric cancer * GSDME * pyroptosis * APG-1252