EGFR-TKIs Induced DPP4 Drives Metabolic Reprogramming of Persister Cells in Lung Cancer

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.