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EGFR-TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer
Yuanzhou Zhang1, Xiaojun Zhang1, Xupeng Yang2
1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Targeting dipeptidyl peptidase 4 (DPP4) with sitagliptin can overcome drug tolerance in EGFR-mutant lung cancer. This combination therapy reduces residual disease and recurrence, improving survival in mice.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Epidermal growth factor receptor (EGFR) mutations drive lung cancer, with cells entering a drug-tolerant persister (DTP) state before resistance to EGFR-tyrosine kinase inhibitors (TKIs).
- Understanding the metabolic adaptations of DTP cells is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To identify therapeutic targets in DTP lung cancer cells.
- To investigate the role of dipeptidyl peptidase 4 (DPP4) in DTP cell metabolism and survival.
- To evaluate the efficacy of combining a TKI with a DPP4 inhibitor.
Main Methods:
- Establishment and characterization of two DTP lung cancer cell lines.
- Analysis of metabolic pathways, including oxidative phosphorylation and fatty acid metabolism.
- Investigation of the DPP4-MEK-Nrf2 signaling pathway.
- In vivo studies combining osimertinib (EGFR-TKI) with sitagliptin (DPP4 inhibitor).
Main Results:
- DPP4 was identified as a key target in DTP cells, which rely on oxidative phosphorylation and enhanced fatty acid metabolism.
- DPP4 facilitates fatty acid uptake and oxidation via CPT1A and maintains mitochondrial function through the DPP4-MEK-Nrf2 pathway.
- Combination therapy with osimertinib and sitagliptin suppressed tumor progression, reduced residual disease, and lowered recurrence rates in mice.
Conclusions:
- DPP4 is a critical mediator of metabolic adaptation and survival in EGFR-TKI-tolerant lung cancer cells.
- Targeting DPP4 in combination with EGFR-TKIs offers a promising strategy to eliminate persister cells and prevent recurrence.
- This approach holds potential for improving long-term outcomes in lung cancer patients.
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