State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.
Department of Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute.
EBioMedicine. 2022 Sep;83:104200. doi: 10.1016/j.ebiom.2022.104200. Epub 2022 Aug 3.
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.
Circulating tumor DNA-based sequencing data of 1153 patients with osimertinib resistance were collected to illustrate the prevalence of EGFR L792F mutation. Sensitivity to osimertinib was tested with constructed EGFR 19Del/T790M-cis-L792F cell lines in vitro and in vivo. The correlation and linked pathways between M2 macrophage polarization and EGFR L792F-induced osimertinib resistance were investigated. Possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored.
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.
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.
This work was supported by the National Natural Science Foundation of China (81871889, 82072586, 81902910), Beijing Natural Science Foundation (7212084, 7214249), the China National Natural Science Foundation Key Program (81630071), the National Key Research and Development Project (2019YFC1315704), CAMS Innovation Fund for Medical Sciences (CIFMS 2021-1-I2M-012), Aiyou Foundation (KY201701) and CAMS Key Laboratory of translational research on lung cancer (2018PT31035).
非小细胞肺癌患者对奥希替尼耐药时，EGFR L792F 错义改变的机制尚未充分阐明。我们旨在探索获得性 L792F 突变导致奥希替尼耐药的关键分子事件和应对策略。
收集了 1153 例奥希替尼耐药患者的基于循环肿瘤 DNA 的测序数据，以说明 EGFR L792F 突变的流行情况。在体外和体内构建 EGFR 19Del/T790M-cis-L792F 细胞系，检测奥希替尼的敏感性。研究了 M2 巨噬细胞极化与 EGFR L792F 诱导的奥希替尼耐药之间的相关性和关联途径。探讨了通过靶向 IL-4 或 STAT3 抑制奥希替尼耐药的可能干预措施。
在奥希替尼耐药后获得 T790M 的同时，鉴定出 EGFR L792F 为独立突变，946 例奥希替尼耐药患者中有 5 例存在 EGFR T790M-cis-L792F 突变。转染 EGFR 19Del/T790M-cis-L792F 的细胞系对奥希替尼的敏感性降低，并增强了具有 M2 极化的浸润性巨噬细胞。计算机分析证实了 M2 极化在 EGFR T790M-cis-L792F 突变诱导的奥希替尼耐药中的作用。EGFR T790M-cis-L792F 突变上调了 STAT3 Tyr705 的磷酸化，并促进了其特异性结合到 IL4 启动子上，增强了 IL-4 的表达和分泌，并诱导了巨噬细胞 M2 极化。此外，STAT3/IL-4（SH-4-54 或 dupilumab）阻断抑制了巨噬细胞 M2 极化并使肿瘤对奥希替尼的敏感性降低。
我们的结果证明，靶向 EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 通路可能是抑制 NSCLC 奥希替尼耐药的一种潜在策略。
本工作得到国家自然科学基金（81871889、82072586、81902910）、北京市自然科学基金（7212084、7214249）、中国国家自然科学基金重点项目（81630071）、国家重点研发计划（2019YFC1315704）、中国医学科学院医学与健康科技创新工程（CIFMS 2021-1-I2M-012）、爱佑基金会（KY201701）和中国医学科学院肿瘤医院重点实验室（2018PT31035）的支持。
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