Targeting inosine metabolism to enhance EGFR-targeted therapy in lung adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for EGFR-mutant lung adenocarcinoma (LUAD).
• Acquired resistance to EGFR-TKIs remains a major clinical challenge, limiting long-term patient survival.
• Understanding the mechanisms underlying TKI resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the metabolic alterations contributing to EGFR-TKI resistance in LUAD.
• To identify novel molecular targets for overcoming TKI resistance.

Main Methods:

• Metabolomic analysis of TKI-resistant LUAD cells, drug-tolerant persister (DTP) cells, and clinical tumor samples.
• Investigated the role of inosine accumulation and its downstream signaling pathways (adenosine A2A receptor - A2aR, cAMP-PKA-CREB).
• Assessed the impact of purine nucleotide phosphorylase (PNP) modulation and A2aR inhibition on TKI sensitivity in vitro and in vivo models.

Main Results:

• Inosine was significantly accumulated in TKI-resistant LUAD cells, DTP cells, and residual tumors.
• Accumulated inosine activated the A2aR/cAMP-PKA-CREB pathway, enhancing oxidative phosphorylation and promoting TKI resistance.
• Downregulation of PNP was identified as the cause of inosine accumulation; PNP restoration or A2aR inhibition sensitized resistant cells and tumors to EGFR-TKIs, with PNP overexpression also inducing cell death via elevated xanthine, uric acid, and ROS.

Conclusions:

• Inosine accumulation, driven by PNP downregulation, is a key metabolic driver of EGFR-TKI resistance in LUAD.
• Targeting the inosine/A2aR axis represents a promising therapeutic strategy to overcome EGFR-TKI resistance.
• Restoring PNP or inhibiting A2aR can re-sensitize LUAD tumors to EGFR-targeted therapies.