Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis:a multi-omics study with drug exploration

作     者：Mingyao Wang Zhe Zhang Jiangfeng Liu Meiyue Song Tiantian Zhang Yiling Chen Huiyuan Hu Peiran Yang Bolun Li Xiaomin Song Junling Pang Yanjiang Xing Zhujie Cao Wenjun Guo Hao Yang Jing Wang Juntao Yang Chen Wang 

作者机构：State Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengdu 610041China Department of Pulmonary and Critical Care MedicineThe First Hospital of Shanxi Medical UniversityTaiyuan 030001China NHC Key Laboratory of PneumoconiosisTaiyuan 030001China Shanxi Province Key Laboratory of Respiratory DiseaseTaiyuan 030001China Department of Pulmonary and Critical Care MedicineCenter of Respiratory MedicineChina-Japan Friendship HospitalBeijing 100029China Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Xi’an Jiao tong UniversityXi’an 710061China Key Lab of Transplant Engineering and ImmunologyMOHRegenerative Medical Research CenterWest China HospitalSichuan UniversityChengdu 610041China 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2022年第7卷第6期

页      面：2066-2078页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 10[医学] 

基　　金：funded by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS)(grant number:2021-I2M-1-049) National Key Research and Development Program of China Grants(grant numbers:2021YFC2500700) the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(grant number:2021RC31002,2018RC31001). 

主　　题：silicosis SYK drugs 

摘      要：Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease progress.Worse still,there are still challenges to be addressed to fully decipher the intricated pathogenesis.Thus,specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed.In this work,multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents.By utilizing an unbiased and time-resolved analysis of the transcriptome,proteome and phosphoproteome of a silicosis mouse model,we have verified the significant differences in transcript,protein,kinase activity and signaling pathway level during silicosis progression,in which the importance of essential biological processes such as macrophage activation,chemotaxis,immune cell recruitment and chronic inflammation were emphasized.Notably,the phosphorylation of EGFR(p-EGFR)and SYK(pSYK)were identified as potential therapeutic targets in the progression of silicosis.To inhibit and validate these targets,we tested fostamatinib(targeting SYK)and Gefitinib(targeting EGFR),and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis.Overall,our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.