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

锡克 矽肺 医学 炎症 吉非替尼 个性化医疗 免疫学 癌症研究 药理学 生物信息学 癌症 表皮生长因子受体 生物 受体 病理 酪氨酸激酶 内科学
作者
Mingyao Wang,Zhe Zhang,Jiangfeng Liu,Meiyue Song,Tiantian Zhang,Yi‐Ling Chen,Huiyuan Hu,Peiran Yang,Bolun Li,Xiaomin Song,Junling Pang,Yanjiang Xing,Zhujie Cao,Wenjun Guo,Hao Yang,Juntao Yang,Jing Wang,Chen Wang
出处
期刊:Signal Transduction and Targeted Therapy [Springer Nature]
卷期号:7 (1) 被引量:32
标识
DOI:10.1038/s41392-022-00959-3
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 (p-SYK) 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.
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