| 摘要: |
| 目的 基于网络药理学初探表皮生长因子受体（EGFR）突变非小细胞肺癌（NSCLC）与酪氨酸激酶抑制剂（TKI）相关皮疹间的关联机制并预测潜在中药。方法 利用基因表达汇编数据库收集使用TKI厄洛替尼处理前后EGFR突变NSCLC细胞、正常成纤维细胞的基因芯片数据，用R 4.3.2软件limma包筛选差异表达基因，用venn包筛选交集靶基因，用ClusterProfiler包对差异表达基因及交集靶基因进行功能富集分析。通过CoreMine Medical数据库对交集靶基因进行潜在中药预测，统计性味归经，并利用分子对接方法进行验证。结果 筛选出126个交集靶基因，基因本体、京都基因与基因组百科全书富集分析提示差异表达基因及交集靶基因均富集在染色体、纺锤体等区域，参与有丝分裂、DNA复制等生物学过程及DNA复制、溶酶体、细胞循环等相关信号通路。基因集富集分析显示厄洛替尼处理后，NSCLC细胞的趋化因子通路、核苷酸结合寡聚域样受体信号通路等被激活，成纤维细胞哺乳动物雷帕霉素靶蛋白信号通路、氨基酸代谢通路出现扰动。通过CoreMine Medical数据库预测了354种主要性属寒、温、平，味属苦、辛、甘，归胃、肺、肝经的中药。以黄芩为例筛选有实验支持的靶基因及对应活性成分并进行分子对接分析，发现靶基因与活性成分结合性能好。结论 EGFR突变NSCLC、TKI相关皮疹在发病机制上具有同源性，均涉及DNA复制、细胞循环等，可为EGFR突变NSCLC伴TKI相关皮疹患者的临证用药提供指导。 |
| 关键词: 非小细胞肺癌 表皮生长因子受体 皮疹 酪氨酸激酶抑制剂 中药 |
| DOI：10.16781/j.CN31-2187/R.20230354 |
| 投稿时间：2023-06-25修订日期：2023-10-07 |
| 基金项目:武汉市卫生健康科研基金（WZ22Q46）. |
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| Association of EGFR mutant non-small cell lung cancer with TKI-related rash and prediction of potential traditional Chinese medicine based on network pharmacology |
| WU Lulu1*,LÜ Xiuwei2 |
(1. Department of Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430014, Hubei, China;
2. Department of Chinese Medicine, Rocket Force Medical Center of PLA, Beijing 100088, China
* Corresponding author) |
| Abstract: |
| Objective To explore the association of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor (TKI)-related rash based on network pharmacology and to predict the potential traditional Chinese medicine. Methods Gene chip data of EGFR mutant NSCLC cell lines and normal fibroblasts before and after treatment with erlotinib, a TKI, were collected from Gene Expression Omnibus database. Differentially expressed genes were screened using limma package of R 4.3.2 software. Cross-over target genes were screened using venn package. The differentially expressed genes and cross-over target genes were analyzed using ClusterProfiler package. CoreMine Medical database was used to predict traditional Chinese medicine of the cross-over target genes, and the nature, flavour, and channel tropism were analyzed. The results were verified by molecular docking method. Results A total of 126 cross-over target genes were screened. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the differentially expressed genes and cross-over target genes were enriched in chromosome, spindle and other regions, and were involved in biological processes such as mitosis and DNA replication. These genes were also associated with signaling pathways including DNA replication, lysosomes, and cell cycle. Gene set enrichment analysis results showed that chemokine pathway and nucleotide-binding oligomerization domain-like receptor signaling pathway were activated in the NSCLC cells, and mammalian target of rapamycin signaling pathway and amino acid metabolic pathway were disturbed in the fibroblasts after treatment with erlotinib. CoreMine Medical database predicted that 354 kinds of traditional Chinese medicines were mainly classified as cold, warm and flat, bitter, pungent and sweet, belonging to stomach, lung and liver meridians. Taking Scutellaria baicalensis as an example, molecular docking analysis of experimentally validated target genes and their active components revealed strong binding interactions between the target genes and active components. Conclusion EGFR mutant NSCLC and TKI-related rash have homology in pathogenesis, both involving DNA replication and cell cycle, which provides traditional Chinese medicine medication instruction for patients with EGFR mutant NSCLC and TKI-related rash. |
| Key words: non-small cell lung cancer epidermal growth factor receptor rash tyrosine kinase inhibitor traditional Chinese medicine |
