Abstract P82: An ATP–P2Y2–Integrin Signaling Axis Underlies the Persistent Stability of Oncogenic EGFR Mutants in non-small cell lung cancer (NSCLC)

Abstract

Activating mutations in the epidermal growth factor receptor (EGFR) gene are key oncogenic drivers in NSCLC. While EGFR tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape, resistance inevitably emerges—often through secondary or tertiary EGFR mutations. These mutant receptors are ligand-independent, evade degradation, and exhibit enhanced stability, yet the molecular basis of their persistent signaling remains poorly defined. To address this gap, we conducted a genome-wide RNAi screen to identify genes that selectively regulate the stability of mutant EGFR. Among the top candidates, we identified P2Y2 receptor, a purinergic G-protein coupled receptor, as a key stabilizer of oncogenic EGFR. Mechanistic studies revealed that EGFR mutants elevate extracellular ATP, which activates P2Y2 and triggers the formation of a cell surface complex involving P2Y2, integrins, and mutant EGFR. This complex protects EGFR from degradation and sustains downstream oncogenic signaling. Importantly, disruption of this P2Y2–integrin–EGFR axis destabilizes activating mutants of EGFR, sensitizes cells to TKI treatment, and suppresses tumor-promoting signals. Analysis of patient datasets revealed frequent co-upregulation of P2Y2 and integrin β1 in NSCLC tumors, underscoring the clinical relevance of this pathway. Our findings uncover a novel, self-reinforcing mechanism through which EGFR mutants actively remodel their microenvironment—by increasing extracellular ATP—to engage P2Y2–integrin axis that enhances their own stability. This previously unrecognized mechanism offers a promising therapeutic opportunity to overcome TKI resistance by targeting the extracellular purinergic signaling network.