Mechanisms of and therapeutic approaches for overcoming resistance to epidermal growth factor receptor (EGFR)-targeted therapy in squamous cell carcinoma of the head and neck (SCCHN).PDF

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1、OralOncologyxxx(2015)xxx–xxxContentslistsavailableatScienceDirectOralOncologyjournalhomepage:www.elsevier.com/locate/oraloncologyMechanismsofandtherapeuticapproachesforovercomingresistancetoepidermalgrowthfactorreceptor(EGFR)-targetedtherapyinsquamouscellcarcinomaoftheheadandneck(SCC

2、HN)ab,⇑KatharineA.R.Price,EzraE.W.CohenaDivisionofMedicalOncology,MayoClinic,Rochester,MN,USAbSectionofHematology/Oncology,DepartmentofMedicine,UniversityofChicago,Chicago,IL,USAarticleinfosummaryArticlehistory:Themajorityofsquamouscellcarcinomaoftheheadandneck(SCCHN)overexpressepide

3、rmalgrowthReceived22April2014factorreceptor(EGFR),whichhasbeenassociatedwithpoortreatmentresponseandsurvival.However,Receivedinrevisedform19January2015onlymodestsuccesshasbeenachievedwiththeuseofsingleagentsthattargetEGFR,possiblyduetoAccepted28January2015primaryandacquiredresistance

4、.ThisreviewwilldiscusskeymechanismsofandtherapeuticapproachesAvailableonlinexxxxtoovercomingresistancetoEGFR-targetedtherapyinSCCHN.Recentpreclinicalandclinicalinvestiga-tionshavedemonstratedthatotherErbBfamilyreceptors(eg,HER2andHER3)andotherhorizontalKeywords:resistancemechanisms,a

5、swellasactivationofdownstreamsignalingpathways,epigeneticevents,EpidermalgrowthfactorreceptorandnuclearEGFRarepossiblemediatorsofresistancetoanti-EGFRtherapeutics.KeydownstreamMoleculartargetedtherapySquamouscellcarcinomaoftheheadandpathwaysthatmaybeimplicatedinEGFRresistanceincludep

6、hosphatidylinositol-3-kinase/proteinneckkinaseB,vascularendothelialgrowthfactor(VEGF),andmammaliantargetofrapamycin(mTOR).ClinicaltrialMultipleagentsthattargetEGFRandotherErbBfamilymembers(ie,lapatinib,afatinib,anddacomitinib),DrugresistanceaswellascombinationtherapiesthattargetEGFRa

7、ndselectedotherpathways(eg,VEGF,mTOR,andHER2c-Met)arebeinginvestigatedclinically.Inaddition,severalphaseIIandIIItrialscontinuetoinvestigateHER3strategiestoenhancetheefficacyofEGFR-targetedtherapyinSCCHN.Ó2015ElsevierLtd.Allrightsreserved.Introductionepidermalgrowthfactorreceptor1[HER1

8、])[1],whichh