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). 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.