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1、EGFRTyrosineKinaseInhibitorsActivateAutophagyasaCytoprotectiveResponseinHumanLungCancerCells1112314WeidongHan,HongmingPan*,YanChen,JieSun,YanshanWang,JingLi,WeitingGe,Lifeng22312Feng,XiaoyingLin,XiaojiaWang,XianWang,HongchuanJin*1DepartmentofMedicalOncology,BiomedicalResearchCent
2、er,SirRunRunShawHospital,SchoolofMedicine,ZhejiangUniversity,Hangzhou,Zhejiang,China,2LaboratoryofCancerEpigenetics,BiomedicalResearchCenter,SirRunRunShawHospital,SchoolofMedicine,ZhejiangUniversity,Hangzhou,Zhejiang,China,3ZhejiangCancerHospital,ZhejiangChineseMedicalUniversity,
3、Hangzhou,Zhejiang,China,4CancerInstitute,TheSecondAffiliatedHospital,CollegeofMedicine,ZhejiangUniversity,Hangzhou,Zhejiang,ChinaAbstractEpidermalgrowthfactorreceptortyrosinekinaseinhibitorsgefitinibanderlotinibhavebeenwidelyusedinpatientswithnon-small-celllungcancer.Unfortunatel
4、y,theefficacyofEGFR-TKIsislimitedbecauseofnaturalandacquiredresistance.Asanovelcytoprotectivemechanismfortumorcelltosurviveunderunfavorableconditions,autophagyhasbeenproposedtoplayaroleindrugresistanceoftumorcells.Whetherautophagycanbeactivatedbygefitiniborerlotinibandtherebyimpa
5、irthesensitivityoftargetedtherapytolungcancercellsremainsunknown.Here,wefirstreportthatgefitiniborerlotinibcaninduceahighlevelofautophagy,whichwasaccompaniedbytheinhibitionofthePI3K/Akt/mTORsignalingpathway.Moreover,cytotoxicityinducedbygefitiniborerlotinibwasgreatlyenhancedafter
6、autophagyinhibitionbythepharmacologicalinhibitorchloroquine(CQ)andsiRNAstargetingATG5andATG7,themostimportantcomponentsfortheformationofautophagosome.Interestingly,EGFR-TKIscanstillinducecellautophagyevenafterEGFRexpressionwasreducedbyEGFRspecificsiRNAs.Inconclusion,wefoundthatau
7、tophagycanbeactivatedbyEGFR-TKIsinlungcancercellsandinhibitionofautophagyaugmentedthegrowthinhibitoryeffectofEGFR-TKIs.AutophagyinhibitionthusrepresentsapromisingapproachtoimprovetheefficacyofEGFR-TKIsinthetreatmentofpatientswithadvancednon-small-celllungcancer.Citation:HanW,PanH
8、,ChenY,SunJ,WangY,etal.(2011)EGFRTyrosin
