ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1530492
This article is part of the Research TopicThe Molecular Mechanism in Anti-tumor Therapy ResistanceView all 16 articles
Targeting PGK1 as a Novel Strategy to Regulate the Sensitivity of HER2 Positive Gastric Cancer to Lapatinib
Provisionally accepted
Xiaochen Ni*
Kaiyuan Zhang
Mingsi ZhangJianing GuoWei Fan
Chuhang Wang
Zhongyan Du
Tao Jiang
Guangji Zhang- School of Basic Medical Sciences and School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
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Abstract: HER2 is amplified in approximately 20% of gastric cancers, and these patients exhibit afavorable response to trastuzumab treatment. Lapatinib, as a HER2-targeted drug, demonstratespotent inhibitory effects on HER2-addicted N87 gastric cancer cells. However, lapatinib has notshown significant advantages in clinical trials. Our study revealed that the expression of the keyglycolysis gene PGK1 negatively correlates with the sensitivity of tumor cells to lapatinib. Bothgenetic regulation of PGK1 and pharmacological inhibition of lactate secretion can enhance theinhibitory effect of lapatinib on N87 cells, whereas overexpression of PGK1 attenuates the efficacyof lapatinib. Modulating PGK1 expression in N87 cells exposed to lapatinib affects the activationlevel of AKT, a downstream effector of HER2, and consequently influences the viability of N87cells. This study indicates that regulating the expression levels of PGK1 impacts the sensitivity ofHER2-positive gastric cancer to lapatinib, and potentially serving as a therapeutic strategy forHER2-positive gastric cancer patients who do not respond to lapatinib.
Keywords: Glycolysis, PGK1, lapatinib, HER2 gastric cancer, Lactate
Received: 19 Nov 2024; Accepted: 15 Jul 2025.
Copyright: © 2025 Ni, Zhang, Zhang, Guo, Fan, Wang, Du, Jiang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaochen Ni, School of Basic Medical Sciences and School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
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