目的 Drug resistance to epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKIs)is the main obstacle for clinical efficacy of EGFR-mutant lung cancer patients.The apoptotic gene BIM plays important role in EGFR-TKIs resistance.Histone deacetylase inhibitor(HDACi)could significantly increase expression of BIM and overcome TKI resistance in lung cancer with BIM deletion polymorphism,while it has little effect in BIM wile type lung cancer cells.Metformin was found to increase BIM expression and inhibit expression of anti-apoptosis protein MCL-1 and BCL-2 in various lung cancer cells.The current study aims to study the effect and mechanisms of metformin combining with HDACi on TKI resistance.方法 We analyzed the effect of metformin combining with HDACi on reversing TKI resistance in several TKI resistant cells with different resistance mechanism(PC-9GR,H1650-M3 and H1975)using MTT,BrdUrd incorporation assay,invasion assay,flow cytometry analysis,immunostaining,and western blot analysis.结果 We showed that combined use of metformin and HDACi synergistically increased the sensitivity of TKI-resistant lung cancer cells to gefitinib,as evidenced by significantly decreased proliferation,invasion and enhanced apoptosis.HDACi increased expression level of pro-apoptosis proteins BIM and BAX in TKI-resistant lung cancer cells in varying degrees,and triggered autophagy.Inhibition of autophagy potentiated HDACi and gefitinib induced cell death.Metformin combining with HDACi further increased expression level of BIM and BAX,meanwhile,remarkably decreased the expression of anti-apoptosis proteins Bcl-xl and Mcl-1.Furthermore,metformin efficiently suppressed autophagy which had been activated by HDACi.结论 There was synergism between metformin and HDACi on TKI sensitivity,this concomitant regimen may be generally adoptted to overcome TKI resistance.