Abstract
BackgroundChinese 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.MethodsA 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.ResultsThe 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.ConclusionsThis study provided a workflow for understanding mechanism of CHM for against drug resistance.
Highlights
Chinese traditional herbal medicine Fuzhengkangai (FZKA) formulation combination with gefitinib can overcome drug resistance and improve the prognosis of lung adenocarcinoma patients
Design of workflow For investigating the mechanism of FZKA in Epidermal growth factor receptor (EGFR)-TKI resistance in molecular level, a hypothesis was proposed, which assumes that targets of bioactive compounds may involve in some pathways that against the EGFR-TKI
The prognosis of overlap was validated in lung adenocarcinoma (LUAD) patients with EGFR mutation form the cancer genome atlas (TCGA) database
Summary
Chinese traditional herbal medicine Fuzhengkangai (FZKA) formulation combination with gefitinib can overcome drug resistance and improve the prognosis of lung adenocarcinoma patients. Bing et al BMC Complementary and Alternative Medicine (2018) 18:293 exon 19 and L858R missense mutation of exon 21 [5] They are effective for early treatment of LUAD, patients will soon have drug resistance in 4 to 12 months during therapy process [2]. The most frequently studied mechanism of acquired resistance is the T790 M point mutation in exon 2 of EGFR [6, 7]. In histologic transformation, the small cell of LUAD histologic transformation and epithelial-mesenchymal transition (MET) activation were closely associated with the acquired EGFR-TKI resistance in patients with never smoked [8,9,10,11]. How to overcome various anti-drug mechanisms is the focus of attention of many scientists
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