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

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for treating EGFR-mutant lung adenocarcinoma (LUAD), resistance significantly impairs their therapeutic effect. In this study, we explored the metabolic features associated with EGFR-TKI resistance and identified the nucleoside inosine as being significantly accumulated in TKI-resistant cells, drug-tolerant persister (DTP) cells, and clinical TKI-residual tumors. Mechanically, accumulated inosine activated the adenosine A_2A receptor (A2aR) and the cAMP-PKA-CREB signaling pathway, thereby enhancing Oxidative Phosphorylation and TKI resistance. Additionally, we identified that inosine secreted by TKI-resistant cells also induced M2-like reprogramming of macrophages. Downregulated purine nucleotide Phosphorylase (PNP) was identified as the pivotal factor for the accumulation of inosine. Overexpression of PNP in TKI-resistant cells not only increased sensitivity of TKI-resistant cells to EGFR-TKIs, but also induced cell death by elevating toxic xanthine, uric acid, and ROS production. Furthermore, overexpression of PNP or using taminadenant, a A2aR-targeting inhibitor used in clinical trials, significantly enhances the EGFR-targeted therapeutic response in vitro, as well as in patient-derived organoids, cell-derived xenografts and mouse models bearing human EGFR-driven spontaneous lung tumor. Overall, our findings clarify the role of inosine metabolism in TKI resistance, highlighting a potential therapeutic strategy-targeting the inosine/A2aR axis-to counteract EGFR-TKI tolerance in LUAD treatment.

Inosine; Lung adenocarcinoma; Macrophage; Metabolic reprogramming.