EGFR and Downstream Genetic Alterations in KRASandAKT Pathwaysin Colorectal CancerforTargetedTherapy.docx
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EGFR and Downstream Genetic Alterations in KRASandAKT Pathwaysin Colorectal CancerforTargetedTherapy.docx
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EGFRandDownstreamGeneticAlterationsinKRASandAKTPathwaysinColorectalCancerforTargetedTherapy
EGFRandDownstreamGeneticAlterationsinKRAS/BRAFandPI3K/AKTPathwaysinColorectalCancer—ImplicationsforTargetedTherapy
PublishedonSeptember27,2012
Author:
MarianneBerg
Specialty:
Biotechnology
Institution:
DepartmentofSurgery,StavangerUniversityHospital
Address:
Stavanger,N-4068,Norway
Author:
KjetilSoreide
Specialty:
Surgery
Institution:
DepartmentofSurgery,StavangerUniversityHospital
Address:
Stavanger,N-4068,Norway
Abstract:
Thepromiseofindividualizedtreatmentisgraduallybeingfulfilled,andtargetedtherapyisbecomingapowerfulstrategytotreatselectedpatientsbasedontheirmolecularprofile.Formetastaticcolorectalcancer(mCRC)patientsanti-EGFR(epidermalgrowthfactorreceptor)targetedtherapyhasmarkedlyimproveddiseasecontrolandsurvival.However,onlyasubgroupofpatientswithmCRCrespondtoanti-EGFRtreatment,andselectingthepatientswithapositiveeffectfromtreatmentisimportantforboththepatientandthesociety.PatientswithmutationsintheKRASgeneareknownasnon-responderstoanti-EGFRtreatmentand,consequently,KRAStestinghasbeenemployedinroutineclinicalpracticeforpatientselection.However,alargenumberoftheKRASwildtypepatientsdonotrespondtothistreatment.Themolecularmechanismunderlyingresponseisnotfullyunderstood,andothermembersoftheKRAS-BRAFpathwayandPI3K-AKTpathwayareinvestigatedaspredictivebiomarkers.Furthermore,concordanceofmutationstatusofprimarytumorsandtheircorrespondinghepaticorpulmonarymetastases,aswellastreatment-inducedmutations,possessanotherchallengeforproperlytailoringtheappropriatetherapytothispatientgroup.Inthisreview,molecularbiomarkersinvolvedinpredictionofresponsetoanti-EGFRtreatmentarediscussed.
Introduction
Whilecolorectalcancerrepresentsaformidablehealthburdeninthewesternworld,theunderstandingofthediseasefeaturesatamolecularandgeneticlevelhasprogressedoverthepastdecadewithassociatednewmodesoftreatment(BergandSoreide,2011).Consequently,theprognosisofpatientsdiagnosedwithcolorectalcancer(CRC)hasneverbeenbetter.Populationlevelstudieshavedemonstratedasteadyincreaseinlong-termsurvivalaftersurgery(Nedreboetal.,2011).Evenforpatientswithdisseminateddiseasethemedianexpectedlifetimehasincreasedremarkablyfromexpectedmediansurvivalof4-5monthswithbestsupportivecaresome15-20yearsago,toanexpectedmediansurvivalthatnowexceeds>2yearswithcurrentlinesofchemotherapyincludingtheuseofmonoclonalantibodies(Toletal.,2009;VanCutsemetal.,2009).Thecurrentlyusedantibodiesbevacizumab,cetuximabandpanitumumabtargetthevascularendothelialgrowthfactor(VEGF)receptorandtheepidermalgrowthfactorreceptor(EGFR)andtheirsignalingpathways,whicharecrucialfortumorprogressionandmetastasis.Specifically,theemploymentofanti-EGFRantibodiesrepresentsabackboneofthetherapeuticoptionsformetastaticcolorectalcancer(mCRC)withrelevantefficacyinbothfirst-andsecond-linetreatmentregiments.However,thistherapyispoorlyeffectiveorineffectiveinunselectedpatients.MutationsinKRAS,BRAF,andPIK3CAgeneshaverecentlyemergedasthebestpredictivefactorsoflow/absentresponsetoEGFR-targetedtherapy.Astheincreasedknowledgeoftumorheterogeneityandgeneticalterationsprogresses,itexemplifiestheneedforfurtherpersonalizedmedicineinmoderncancermanagement.HerewehighlightsomeofthecurrenttherapeuticviewpointsandfindingsconcerningtheEGFR-pathwayincolorectalcancer(Figure1).
MolecularGuidinginChoiceofTherapy
Figure1.Ligandbindstotheextracellulardomainofthereceptorandresultsinreceptordimerizationandphosphorylationoftheintracellulardomains.ActivatedEGFRleadstoactivationoftheoncogeneKRAS,whichinturnactivatestheoncogeneBRAF,mitogen-activatedproteinkinasekinase(MEK),andmitogen-activatedproteinkinase(MAPK),andleadstoexpressionofgrowth-promotinggenes.InadditiontoactivationofKRAS,EGFRactivatestheoncogenePIK3CAwhichphosphorylatesphosphatidylinositol-2-phosphate(PIP2)tophosphatidylinositol-3-phosphate(PIP3),whichinturnactivatesAKTandseveraldownstreameffectors,leadingtoproteinsynthesis,cellgrowthandsurvival,proliferation,migration,andangiogenesis.
Today,thechoiceoftreatmentforpatientswithtumorsincolonorrectumislargelybasedondiseasestage.Correctstagingofcolorectaltumorsisthereforefundamental.Roughly,patientswithalocalizedcolontumorareprimarilyoperated,wherethosepatientswithmetastasestolymphnodesareofferedadjuvantchemotherapy,iftheirphysicalconditionotherwiseallowsforthistreatment.Thestagingforrectalcancernowfollowsstrictguidelineswithpre-operativemagneticresonanceimagingandneoadjuvantchemoradiationbeforesurgeryinselectedpatients(asreviewedinSoreideetal.,2011).However,theclinicopathologicalstaging,whichisusedtoguidethetherapyregimeforapatient,hasweaknessesinpredictionofindividualresponsetotreatment.WhilegivingchemotherapyforstageII(negativenode)diseaseisconsideredcontroversial,survivaldataforstageIIpatientsmaysuggestthatasubgroupwouldbenefitfromadjuvanttreatment,asabout15%developrecurrenceanddiefromdisease.Furthermore,whileallstageIIIpatientsthatarephysicallyfitareconsideredforadjuvantchemotherapy,somemayhaveadverseside-effectsfromadjuvantchemotherapyyetbeingataverysmallriskforrecurrentdisease.Basedontheseobservations,itisclearthattheapproachtoadjuvantchemotherapyfortheindividualpatientisratherblunt,andbetterandmoreaccuratetoolstotailortherapyareneeded.
Forpatientsdiagnosedwithametastaticcolorectaldiseasetheadjuvanttreatmentregimeismonoclonalantibodies(mAbs)directedagainsttheEGFR(Figure2B).Bindingofantibodiestothereceptorinhibitsligandbinding.ThedownstreamRAS/RAF/MAPKpathwayandPI3K/PTEN/AKTpathwayarethusinhibited,resultingininhibitionofcellgrowthandproliferation,cellcyclearrest,and/orapoptosis.However,theseagentshaveshowntobeeffectiveinonlyaminorityofthepatients.Initially,patientswereselectedformAbstreatmentbasedonimmunohistochemicaldetectionofEGFR,butthiswasshowntobeapoormarker(Chungetal.,2005).ApreselectionofcolorectalpatientswithwildtypeKRASgenotypeincreasesthetherapeuticefficacyofanti-EGFRmonoclonalantibodies(Lievreetal.,2006),andKRASmutationalstatusofcodons12and13isnowinvestigatedonaroutinebasisbeforeadministrationofEGFRtherapy.However,notallKRAScodon12/13wildtypepatientshavearesponsetotreatment,andothermutationsinKRASaswellasthedownstreamtargetsBRAF,PIK3CA,andPTENhavebeensuggestedasbeingcausativeforthelackofresponse.Theneedforbetterstratificationofpatients,especiallythoseeligibleforadjuvanttreatment,isimportant.
PredictionofResponsetoChemotherapy
Figure2.A.TheEGFRisactivatedbyligandbindingtotheextracellulardomain,whichresultsinactivationasaresultofautophosphorylationofkeytyrosineresiduesintheintracellulardomain.B.Monoclonalantibodies(mAbs,suchascetuximabandpanitumumab)bindtotheextracellulardomainoftheEGFRandhinderbindingofligands.Signalingthroughthereceptorisabrogated.C.Smallmoleculartyrosinekinases(TKIs,suchaserlotinibandgefitinib)prohibitphosphorylationoftheEGFRandthetyrosinekinasedomainofthereceptorisnotactive.
Scientificreportssupportthefactthatinter-individualdifferencessuchasinheritedpolymorphismsandsomaticmutations,aswellastumor-specificaberrations,willinfluencetheeffectoftreatmentwithdrugs(Ebertetal.,2012;Lievreetal.,2006;WalkoandMcLeod,2012).Whilethismayinsomeinstancesposerestrictionsineffectivenessforcertaindrugstosomepatients,itmayalsoposenewmodesoftargetingotherpatientsthatwillrespond.Forexample,patientswhohavecolorectalcancerwithTFAP2Ehypermethylation,targetingDKK4maybeanoptiontoovercomeTFAP2E-mediateddrugresistance(Ebertetal.,2012).Amoreindividual-basedtreatmentregimenisthereforerequiredtodefinerespondersandnon-responderstoavoidinsufficientorunnecessarytreatment.Predictingoutcomeoftreatmenthasobviousbenefits.Notonlyforthepatient,asnon-responderscanavoidthetoxicitiesandunwantedside-effects,butitmayalsorepresenteconomicadvantageforthehealthsystem,asexpensivemedicationwillonlybeadministeredtothosewhowillactuallybenefitfromanyspecifictreatment.
TreatmentDirectedTowardstheEpidermalGrowthFactorReceptor(EGFR)
Epidermalgrowthfactorreceptorsignalingisaresponseofbindingofcytokines,hormones,and/orgrowthfactorstotheextracellulardomainofthereceptor(Figure2A).TheEGFRisamemberofthefamilyofreceptortyrosinekinases(Figure3),andthegeneisconsideredanoncogene.EGFRactivationresultsinsignalingthroughtheMAPkinasepathway,andthroughthePI3K/AKTpathway,causingcellulargrowthandprogression,proliferation,angiogenesis,andinvasion.EGFRexpressionisreportedtobeelevatedin60-80%ofcolorectaltumors,investigatedusingimmunohistochemistry(IHC)(GoldsteinandArmin,2001)butisgenerallynotconsideredagoodpredictivemarker(Yangetal.,2012).
Figure3.AschematicoverviewoftheEGFRanditsbindingtoligand(magenta).
Themonoclonalantibodiescetuximab(Erbitux®)andpanitumumab(Vectibix®)selectivelybindtoth
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