EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer
Abstract Mutations in epidermal growth factor receptor (EGFR) are the key drivers of lung cancer initiation and recurrence. The cancer cells undergo transformation to a reversible drug‐tolerant persister (DTP) state prior to the development of resistance against EGFR‐tyrosine kinase inhibitors (TKIs...
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| Format: | Article |
| Language: | English |
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202506950 |
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| author | Yuanzhou Zhang Xiaojun Zhang Xupeng Yang Xingshi Chen Yuehong Wang Jingying Hu Rui Liu Xiaoying Luo |
| author_facet | Yuanzhou Zhang Xiaojun Zhang Xupeng Yang Xingshi Chen Yuehong Wang Jingying Hu Rui Liu Xiaoying Luo |
| author_sort | Yuanzhou Zhang |
| collection | DOAJ |
| description | Abstract Mutations in epidermal growth factor receptor (EGFR) are the key drivers of lung cancer initiation and recurrence. The cancer cells undergo transformation to a reversible drug‐tolerant persister (DTP) state prior to the development of resistance against EGFR‐tyrosine kinase inhibitors (TKIs). Two DTP lung cancer cells with different proliferative capacities are established and identified dipeptidyl peptidase 4 (DPP4) as a potential therapeutic target. The DTP cells primarily relied on oxidative phosphorylation, which is accompanied by the up‐regulation of fatty acid metabolism. Mechanistically, DPP4 facilitates the uptake of fatty acids via carnitine palmitoyl transferase 1a (CPT1A, and enhances fatty acid oxidation. In addition, the DPP4‐mitogen‐activated protein kinase kinase (MEK)‐Nuclear factor erythroid‐2‐related factor 2 (Nrf2) signaling pathway maintains mitochondrial function by activating the antioxidant pathway. The combination of osimertinib and sitagliptin, a DPP4 inhibitor, not only suppressed tumor progression but also reduced the number of residual tumor cells and minimal residual disease. Notably, this combination therapy significantly lowered recurrence rates and extended the survival of tumor‐bearing mice compared to the monotherapies. The study provides new insights into the metabolic adaptations of DTP lung cancer cells in response to EGFR‐TKIs, offering novel therapeutic strategies for targeting these persister cells. |
| format | Article |
| id | doaj-art-0386556f4b834176a0160497f53d25b6 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-0386556f4b834176a0160497f53d25b62025-08-23T14:13:41ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202506950EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung CancerYuanzhou Zhang0Xiaojun Zhang1Xupeng Yang2Xingshi Chen3Yuehong Wang4Jingying Hu5Rui Liu6Xiaoying Luo7State Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaState Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Liver Surgery and Transplantation and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education) Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Thoracic Surgical Oncology Shanghai Lung Cancer Center Shanghai Chest Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaState Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaState Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaState Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaState Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaAbstract Mutations in epidermal growth factor receptor (EGFR) are the key drivers of lung cancer initiation and recurrence. The cancer cells undergo transformation to a reversible drug‐tolerant persister (DTP) state prior to the development of resistance against EGFR‐tyrosine kinase inhibitors (TKIs). Two DTP lung cancer cells with different proliferative capacities are established and identified dipeptidyl peptidase 4 (DPP4) as a potential therapeutic target. The DTP cells primarily relied on oxidative phosphorylation, which is accompanied by the up‐regulation of fatty acid metabolism. Mechanistically, DPP4 facilitates the uptake of fatty acids via carnitine palmitoyl transferase 1a (CPT1A, and enhances fatty acid oxidation. In addition, the DPP4‐mitogen‐activated protein kinase kinase (MEK)‐Nuclear factor erythroid‐2‐related factor 2 (Nrf2) signaling pathway maintains mitochondrial function by activating the antioxidant pathway. The combination of osimertinib and sitagliptin, a DPP4 inhibitor, not only suppressed tumor progression but also reduced the number of residual tumor cells and minimal residual disease. Notably, this combination therapy significantly lowered recurrence rates and extended the survival of tumor‐bearing mice compared to the monotherapies. The study provides new insights into the metabolic adaptations of DTP lung cancer cells in response to EGFR‐TKIs, offering novel therapeutic strategies for targeting these persister cells.https://doi.org/10.1002/advs.202506950DTPDPP4EGFR‐Tkilung cancerOXPHOS |
| spellingShingle | Yuanzhou Zhang Xiaojun Zhang Xupeng Yang Xingshi Chen Yuehong Wang Jingying Hu Rui Liu Xiaoying Luo EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer Advanced Science DTP DPP4 EGFR‐Tki lung cancer OXPHOS |
| title | EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer |
| title_full | EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer |
| title_fullStr | EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer |
| title_full_unstemmed | EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer |
| title_short | EGFR‐TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer |
| title_sort | egfr tkis induced dpp4 drives metabolic reprogramming of persister cells in lung cancer |
| topic | DTP DPP4 EGFR‐Tki lung cancer OXPHOS |
| url | https://doi.org/10.1002/advs.202506950 |
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