ERK/GATAD2A/SAA1 axis drives osimertinib resistance via NF-κB and macrophage reprogramming in EGFR-mutated lung adenocarcinoma
- 1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University
- 2Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
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.
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BibTeX
@article{zhu2026erkgatad2asaa1,
title = {{ERK/GATAD2A/SAA1 axis drives osimertinib resistance via NF-κB and macrophage reprogramming in EGFR-mutated lung adenocarcinoma}},
author = {Junkan Zhu and Shencheng Ren and Tao Cheng and Guangyao Shan and Han Lin and Xiaolong Huang and Yunyi Bian and Lewei Duan and Yidu Hu and Yingting Wu and Dejun Zeng and Yongqiang Ao and Jiaqi Liang and Shuai Wang and Cheng Zhan},
journal = {Journal of Experimental \& Clinical Cancer Research},
year = {2026},
month = jul,
doi = {10.1186/s13046-026-03792-6},
url = {https://doi.org/10.1186/s13046-026-03792-6},
note = {CC BY},
}
RIS
TY - JOUR
TI - ERK/GATAD2A/SAA1 axis drives osimertinib resistance via NF-κB and macrophage reprogramming in EGFR-mutated lung adenocarcinoma
AU - Junkan Zhu
AU - Shencheng Ren
AU - Tao Cheng
AU - Guangyao Shan
AU - Han Lin
AU - Xiaolong Huang
AU - Yunyi Bian
AU - Lewei Duan
AU - Yidu Hu
AU - Yingting Wu
AU - Dejun Zeng
AU - Yongqiang Ao
AU - Jiaqi Liang
AU - Shuai Wang
AU - Cheng Zhan
PY - 2026
DA - 2026/07/01
JO - Journal of Experimental & Clinical Cancer Research
DO - 10.1186/s13046-026-03792-6
UR - https://doi.org/10.1186/s13046-026-03792-6
AB - 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.
SN - 1756-9966
ER -