Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization

作者：Yiting Sun, Yiting Dong, Xijuan Liu, Yundi Zhang, Hua Bai, Jianchun Duan, Zhihua Tian, Yan Xiang, Jie Wang, Zhijie Wang · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104200 · 被引用次数：34 · 研究领域：Lung Cancer Treatments and Mutations、Cytokine Signaling Pathways and Interactions、Cancer Immunotherapy and Biomarkers

BACKGROUND: The mechanism of missense alteration at EGFR L792F in patients with non-small cell lung cancer resistant to osimertinib has not been sufficiently clarified. We aimed to explore the critical molecular events and coping strategies in osimertinib resistance due to acquired L792F mutation. METHODS: -induced osimertinib resistance were investigated. Possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored. FINDINGS: The concomitant EGFR L792F was identified as an independent mutation following the acquisition of T790M after osimertinib resistance, in that 5 of the 946 patients with osimertinib resistance harbored EGFR T790M-cis-L792F mutation. Transfected EGFR 19Del/T790M-cis-L792F in cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. Silico analyses confirmed the role of M2 polarization in osimertinib resistance induced by EGFR T790M-cis-L792F mutation. EGFR T790M-cis-L792F mutation upregulated phosphorylation of STAT3 Tyr705 and promoted its specific binding to IL4 promoter, enhancing IL-4 expression and secretion and inducing macrophage M2 polarization. Furthermore, blockade of STAT3/IL-4 (SH-4-54 or dupilumab) suppressed macrophage M2 polarization and regressed tumor sensitivity to osimertinib. INTERPRETATION: Our results proved that targeting EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC. F...