Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via suppressing M2 macrophages polarization
Yiting Sun,
Yiting Dong,
Xijuan Liu,
Yundi Zhang,
Hua Bai,
Jianchun Duan,
Zhihua Tian,
Xiang Yan,
Jie Wang,
Zhijie Wang
Affiliations
Yiting Sun
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
Yiting Dong
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
Xijuan Liu
Department of Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute
Yundi Zhang
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
Hua Bai
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
Jianchun Duan
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
Zhihua Tian
Department of Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute
Xiang Yan
Department of Medical Oncology, The Chinese PLA General Hospital
Jie Wang
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; Corresponding authors at: 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, 17 Pan-jia-yuan South Lane, Chaoyang District, 100021 Beijing, China.
Zhijie Wang
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; Corresponding authors at: 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, 17 Pan-jia-yuan South Lane, Chaoyang District, 100021 Beijing, China.
Summary: 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: 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 L792Fcis-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. Funding: 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).
