Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou, China.
Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, 199 West Donggang Road, Lanzhou, 730000, Gansu, China.
BMC Complement Altern Med. 2018 Nov 6;18(1):293. doi: 10.1186/s12906-018-2347-x.
Chinese traditional herbal medicine Fuzhengkangai (FZKA) formulation combination with gefitinib can overcome drug resistance and improve the prognosis of lung adenocarcinoma patients. However, the pharmacological and molecular mechanisms underlying the active ingredients, potential targets, and overcome drug resistance of the drug are still unclear. Therefore, it is necessary to explore the molecular mechanism of FZKA.
A systems pharmacology and bioinformatics-based approach was employed to investigate the molecular pathogenesis of EGFR-TKI resistance with clinically effective herb formula. The differential gene expressions between EGFR-TKI sensitive and resistance cell lines were calculated and used to find overlap from targets as core targets. The prognosis of core targets was validated from the cancer genome atlas (TCGA) database by Cox regression. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment is applied to analysis core targets for revealing mechanism in biology.
The results showed that 35 active compounds of FZKA can interact with eight core targets proteins (ADRB2, BCL2, CDKN1A, HTR2C, KCNMA1, PLA2G4A, PRKCA and LYZ). The risk score of them were associated with overall survival and relapse free time (HR = 6.604, 95% CI: 2.314-18.850; HR = 5.132, 95% CI: 1.531-17.220). The pathway enrichment suggested that they involved in EGFR-TKI resistance and non-small cell lung cancer pathways, which directly affect EGFR-TKI resistance. The molecular docking showed that licochalcone a and beta-sitosterol can closely bind two targets (BCL2 and PRKCA) that involved in EGFR-TKI resistance pathway.
This study provided a workflow for understanding mechanism of CHM for against drug resistance.
中药扶正康艾配方联合吉非替尼可以克服耐药性，改善肺腺癌患者的预后。然而，药物的活性成分、潜在靶点和克服耐药性的药理和分子机制尚不清楚。因此，有必要探讨 FZKA 的分子机制。
采用基于系统药理学和生物信息学的方法研究具有临床疗效的草药配方对 EGFR-TKI 耐药的分子发病机制。计算 EGFR-TKI 敏感和耐药细胞系之间的差异基因表达，并寻找重叠靶点作为核心靶点。通过 Cox 回归从癌症基因组图谱（TCGA）数据库验证核心靶点的预后。京都基因与基因组百科全书（KEGG）通路富集分析用于分析核心靶点，以揭示生物学中的机制。
结果表明，FZKA 的 35 种活性化合物可以与 8 种核心靶点蛋白（ADRB2、BCL2、CDKN1A、HTR2C、KCNMA1、PLA2G4A、PRKCA 和 LYZ）相互作用。它们的风险评分与总生存期和无复发生存时间相关（HR=6.604，95%CI：2.314-18.850；HR=5.132，95%CI：1.531-17.220）。通路富集表明，它们参与了 EGFR-TKI 耐药和非小细胞肺癌途径，直接影响 EGFR-TKI 耐药性。分子对接表明，甘草查尔酮 A 和β-谷甾醇可以紧密结合两种参与 EGFR-TKI 耐药途径的靶点（BCL2 和 PRKCA）。
本研究为了解中药对抗耐药性的机制提供了一个工作流程。
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