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EGFR inhibition in non-small cell lung cancer current evidence and future directions.doc

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EGFR inhibition in non-small cell lung cancer current evidence and future directions

Chietal.BiomarkerResearch2013,1:2 /content/1/1/2 REVIEW OpenAccess EGFRinhibitioninnon-smallcelllungcancer: currentevidenceandfuturedirections AlexanderChi1*,ScotRemick2andWilliamTse3 Abstract EGFRinhibitionhasemergedtobeanimportantstrategyinthetreatmentofnon-smallcelllungcancer(NSCLC). Smallmoleculetyrosinekinaseinhibitors(TKIs)andmono-clonalantibodies(mAbs)totheEGFRhavebeentested inmultiplelargerandomizedphaseIIIstudiesaloneorcombinedwithchemotherapy,aswellassmallphaseI-II studieswhichinvestigatedtheirefficacyasradiosensitizerswhencombinedwithradiotherapy.Inthisreview,we describedthecurrentclinicaloutcomeaftertreatmentwithEGFRTKIsandmAbsaloneorcombinedwith chemotherapyinadvancedstageNSCLC,aswellastheearlyfindingsinfeasibility/phaseIorIIstudiesregardingto whetherEGFRTKIormAbcanbesafelyandeffectivelycombinedwithradiotherapyinthetreatmentoflocally advancedNSCLC.Furthermore,weexplorethepotentialpredictivebiomarkersforresponsetoEGFRTKIsormAbs inNSCLCpatientsbasedonthefindingsinthecurrentclinicaltrials;themechanismsofresistancetoEGFR inhibition;andthestrategiesofaugmentingtheantitumoractivityoftheEGFRinhibitorsaloneorwhencombined withchemotherapyorradiotherapy. Keywords:EGFR,NSCLC,EGFRmutations,Radiotherapy,Resistance Introduction cytotoxicinsults[1,4].Thismakesitanattractivetargetin The epidermal growth factor receptor (EGFR), a 170 kD cancertherapy;anditsinhibitionastrategyforaugmenta- transmembrane protein consisted of a N-terminus extra- tion of the efficacy of chemotherapy and radiotherapy. cellularligand-bindingsite,ahydrophobictransmembrane SincetheinitialdiscoveryoftheEGFRin1962,aclassof domain, and a C-terminus intracellular region with tyro- antibodiesblockingtheEGFR’sextra-cellularligandbind- sinekinaseactivity,isthefirstoftheErbBfamilyofrecep- ing site to prevent receptor activation, and to down- tor tyrosine kinases (RTKs) [1,2]. The other members regulateEGFRexpressionatthecellsurfacethroughanti- include ErbB2 (HER2/neu), ErbB3 (HER3), and E