Targeting EP2 overcomes osimertinib-tolerant persisters through metabolic and inflammatory reprogramming in non-small cell lung cancer.
TL;DR
Clinically, high expression levels of EP2, phosphorylated GYS1, and HIF-1α in tumor tissues correlated with poor therapeutic response to osimertinib, and elevated serum concentrations of inflammatory cytokines in NSCLC patients, suggesting that EP2 serves as a critical regulator linking metabolic reprogramming and inflammatory signaling to OTPs.
Abstract
Although osimertinib is an effective third-generation EGFR inhibitor for EGFR-mutant NSCLC, the emergence of acquired resistance continues to limit its long-term clinical benefit. However, the early cellular adaptations that allow residual tumor cells to survive osimertinib exposure are not fully understood. Here, we combined patient-derived NSCLC samples, transcriptomic analyses, cellular experiments, and xenograft models to determine whether prostaglandin E2 receptor subtype 2 (EP2) contributes to osimertinib-tolerant persister (OTP) cells. EP2 was markedly upregulated in OTP NSCLC cells and patient-derived tumor tissues. Mechanistically, EP2 activation induced Ser641 site-specific phosphorylation of glycogen synthase (GYS1), which in turn led to aberrant glycogen accumulation, suppressed glycolytic metabolism, and elevated intracellular succinate levels. The accumulated succinate stabilized hypoxia-inducible factor-1α (HIF-1α), thereby driving the transcription of proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). This metabolic-inflammatory feedback loop enhanced cancer cell survival and facilitated the development of OTPs. Additionally, genetic or pharmacologic inhibition of EP2 effectively reversed these pathogenic alterations, restored osimertinib sensitivity in OTP cells, and attenuated tumor growth in xenograft models. Clinically, high expression levels of EP2, phosphorylated GYS1, and HIF-1α in tumor tissues correlated with poor therapeutic response to osimertinib, and elevated serum concentrations of inflammatory cytokines in NSCLC patients. Collectively, EP2 serves as a critical regulator linking metabolic reprogramming and inflammatory signaling to OTPs. These findings suggest that EP2 blockade may serve as a rational combination strategy for limiting early adaptive resistance and improving responses to EGFR-TKIs in EGFR-mutant NSCLC.