Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib
HER2 is amplified in approximately 20% of gastric cancers, and these patients exhibit a favorable response to trastuzumab treatment. Lapatinib, as a HER2-targeted drug, demonstrates potent inhibitory effects on HER2-addicted N87 gastric cancer cells. However, lapatinib has not shown significant adva...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-07-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1530492/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849714504979447808 |
|---|---|
| author | Xiaochen Ni Kaiyuan Zhang Xueru Huang Mingsi Zhang Mingsi Zhang Jianing Guo Wei Fan Chuhang Wang Zhongyan Du Zhongyan Du Tao Jiang Tao Jiang Tao Jiang Guangji Zhang Guangji Zhang Guangji Zhang |
| author_facet | Xiaochen Ni Kaiyuan Zhang Xueru Huang Mingsi Zhang Mingsi Zhang Jianing Guo Wei Fan Chuhang Wang Zhongyan Du Zhongyan Du Tao Jiang Tao Jiang Tao Jiang Guangji Zhang Guangji Zhang Guangji Zhang |
| author_sort | Xiaochen Ni |
| collection | DOAJ |
| description | HER2 is amplified in approximately 20% of gastric cancers, and these patients exhibit a favorable response to trastuzumab treatment. Lapatinib, as a HER2-targeted drug, demonstrates potent inhibitory effects on HER2-addicted N87 gastric cancer cells. However, lapatinib has not shown significant advantages in clinical trials. Our study revealed that the expression of the key glycolysis gene PGK1 negatively correlates with the sensitivity of tumor cells to lapatinib. Both genetic regulation of PGK1 and pharmacological inhibition of lactate secretion can enhance the inhibitory effect of lapatinib on N87 cells, whereas overexpression of PGK1 attenuates the efficacy of lapatinib. Modulating PGK1 expression in N87 cells exposed to lapatinib affects the activation level of AKT, a downstream effector of HER2, and consequently influences the viability of N87 cells. This study indicates that regulating the expression levels of PGK1 impacts the sensitivity of HER2-positive gastric cancer to lapatinib, and potentially serving as a therapeutic strategy for HER2-positive gastric cancer patients who do not respond to lapatinib. |
| format | Article |
| id | doaj-art-ba696e28ff6340a9b242a669f32f3a6d |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-ba696e28ff6340a9b242a669f32f3a6d2025-08-20T03:13:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-07-011610.3389/fphar.2025.15304921530492Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinibXiaochen Ni0Kaiyuan Zhang1Xueru Huang2Mingsi Zhang3Mingsi Zhang4Jianing Guo5Wei Fan6Chuhang Wang7Zhongyan Du8Zhongyan Du9Tao Jiang10Tao Jiang11Tao Jiang12Guangji Zhang13Guangji Zhang14Guangji Zhang15School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Sport, Loughborough University, Loughborough, Leicestershire, United KingdomSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaZhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaZhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Zhejiang, ChinaTraditional Chinese Medicine “Preventing Disease”Wisdom Health Project Research Center of Zhejiang, Zhejiang, ChinaSchool of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, ChinaZhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Zhejiang, ChinaTraditional Chinese Medicine “Preventing Disease”Wisdom Health Project Research Center of Zhejiang, Zhejiang, ChinaHER2 is amplified in approximately 20% of gastric cancers, and these patients exhibit a favorable response to trastuzumab treatment. Lapatinib, as a HER2-targeted drug, demonstrates potent inhibitory effects on HER2-addicted N87 gastric cancer cells. However, lapatinib has not shown significant advantages in clinical trials. Our study revealed that the expression of the key glycolysis gene PGK1 negatively correlates with the sensitivity of tumor cells to lapatinib. Both genetic regulation of PGK1 and pharmacological inhibition of lactate secretion can enhance the inhibitory effect of lapatinib on N87 cells, whereas overexpression of PGK1 attenuates the efficacy of lapatinib. Modulating PGK1 expression in N87 cells exposed to lapatinib affects the activation level of AKT, a downstream effector of HER2, and consequently influences the viability of N87 cells. This study indicates that regulating the expression levels of PGK1 impacts the sensitivity of HER2-positive gastric cancer to lapatinib, and potentially serving as a therapeutic strategy for HER2-positive gastric cancer patients who do not respond to lapatinib.https://www.frontiersin.org/articles/10.3389/fphar.2025.1530492/fullglycolysisPGK1lapatinibHER2 gastric cancerlactate |
| spellingShingle | Xiaochen Ni Kaiyuan Zhang Xueru Huang Mingsi Zhang Mingsi Zhang Jianing Guo Wei Fan Chuhang Wang Zhongyan Du Zhongyan Du Tao Jiang Tao Jiang Tao Jiang Guangji Zhang Guangji Zhang Guangji Zhang Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib Frontiers in Pharmacology glycolysis PGK1 lapatinib HER2 gastric cancer lactate |
| title | Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib |
| title_full | Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib |
| title_fullStr | Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib |
| title_full_unstemmed | Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib |
| title_short | Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib |
| title_sort | targeting pgk1 as a novel strategy to regulate the sensitivity of her2 positive gastric cancer to lapatinib |
| topic | glycolysis PGK1 lapatinib HER2 gastric cancer lactate |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1530492/full |
| work_keys_str_mv | AT xiaochenni targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT kaiyuanzhang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT xueruhuang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT mingsizhang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT mingsizhang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT jianingguo targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT weifan targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT chuhangwang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT zhongyandu targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT zhongyandu targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT taojiang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT taojiang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT taojiang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT guangjizhang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT guangjizhang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib AT guangjizhang targetingpgk1asanovelstrategytoregulatethesensitivityofher2positivegastriccancertolapatinib |