ERK/GATAD2A/SAA1 axis drives osimertinib resistance via NF-κB and macrophage reprogramming in EGFR-mutated lung adenocarcinoma

Abstract Background Acquired resistance significantly limits the long-term clinical benefit of osimertinib in EGFR-mutant lung adenocarcinoma (LUAD). However, the early non-genetic adaptations and microenvironmental crosstalk that enable initial tumor survival remain poorly defined. This study aimed to elucidate the epigenetic-immune mechanisms driving osimertinib resistance and to identify novel actionable therapeutic targets. Methods We integrated transcriptomic profiling and clinical cohort analyses to identify therapy-induced secreted factors during the evolution of EGFR-TKI resistance. The upstream regulatory mechanisms were characterized using ChIP, Co-IP, and dual-luciferase reporter assays. The dual functional roles of the identified factor, serum amyloid A1 (SAA1), in tumor-intrinsic signaling and macrophage polarization were investigated in vitro. Finally, the therapeutic efficacy of combining SAA1 neutralization with osimertinib was evaluated across patient-derived organoids, xenografts, and immunocompetent spontaneous lung tumor models. Results We identified SAA1 as a critical therapy-induced secreted factor that progressively increases during the transition from drug tolerance to established resistance, which negatively correlates with clinical outcomes in patients receiving osimertinib. Mechanistically, osimertinib treatment suppressed the ERK-dependent phosphorylation of the transcriptional repressor GATAD2A at Ser114. This event destabilized the NuRD complex, thereby relieving the epigenetic transcriptional repression of SAA1. Secreted SAA1 promoted therapeutic resistance through dual mechanisms: activating the autocrine TLR4/NF-κB survival signaling in tumor cells and inducing the paracrine polarization of pro-tumorigenic SPP1⁺ macrophages. Therapeutically, targeted neutralization of SAA1 synergized robustly with osimertinib to reverse immunosuppressive remodeling and induce profound tumor regression in multiple preclinical models. Conclusions Our findings define a novel therapy-induced ERK/GATAD2A/SAA1 epigenetic-immune axis that drives acquired resistance to osimertinib. SAA1 acts as a pivotal bridge between tumor-intrinsic survival adaptations and microenvironmental immune suppression, highlighting SAA1 neutralization as a tractable combinatorial strategy to enhance EGFR-TKI efficacy in LUAD.