EGFR抑制剂

EpidermalGrowthFactorReceptor(EGFR)InhibitorsDr.M.JayanthiIntroductionCellularSignallingPathwaysVitalforcellcycleprogression,growth,differentiation&death.GrowthFactors–ThekeystoneAdelicatebalancebetweenactivatingandinhibitorysignalsneedstobemaintainednormallyAlterationinthisbalance-Dysregulatedcellularproliferation&survivalofabnormalcells.GeneTranscriptionG0G1PrimingSG2MCellCycle+GrowthFactors&CellCycleReceptorsEpidermalGrowthFactorReceptor(EGFR)Breast14%-91%Colon25%-77%LungCancer40%-80%(Nonsmallcell)Ovarian35%-70%Pancreatic30%-50%Head&Neck80%-95%EGFRExpressionRateTumourSomeLandmarksinEGFRSignallingStanleyCohenHumanEGF(1970’s)IsolationandcloningofEGFR(1980’s).LinkbetweenEGFRandmalignanttransformationofcellsdemonstratedEGFinmice(1960’s)Mendelsohnetal.,BlockingEGFRsignallingtotreatcancerMurinemonoclonalantibodiestargetingEGFR-TK→Human:murinechimericversionMorethan20anti-EGFRagentsindevelopmentTKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4Nospecificligands-oftenactsasdimerpartnerHeregulinsNRG2NRG3Heregulinsβ-cellulinEGF,TGFa,bCellulinAmphiregulin,HB-EGFHumanEpidermalGrowthFactorReceptorFamilyTKIntracellularDomainTransmembraneDomainExtracellularDomainEGFRStructureTKTKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4EGFRHomoDimerisationEGFRStimulation&dimerisationTKTKTKerbB1HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4HeteroDimerisationRiskforcancerEGFRstimulationcont…TKEGFRFunctioninNormalCellTKATPATPCellProliferationAntiapoptosisAngiogenesisGeneTranscriptionCellCycleProgression+TKTKEGFRsignaltransductionintumourcellsSurvival(anti-apoptosis)PI3-KSTAT3AKTPTENMEKGenetranscriptionMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasispYpYRASRAFSOSGRB2pYG1SMG2MMPαβγPyk2SrcRasMAPKCa++PPerbBLigandGeneTranscription+++HB-EGFSteroidhormoneSteroidhormonereceptorGproteinOthermechanismsofEGFRstimulationEGFR-VariantIIIEGFR–WildTypeNoextracellulardomainPresentLigandcannotbindCanbindTKconstitutivelyactiveTKactivatedbyligandbindingCannotdimeriseCandimeriseNotfoundinnormalcellsFoundnormallyMorepropensityforcancerUpregulationleadstocancerHowEGFRvariantdiffersfromthewildtypeTKGenetranscriptionCellCycleProgressionCellProliferationMetastasisAntiApoptosisCancerATPNormalCellCancerousCellUpRegulationMutationConsequenceofproliferationofEGFRreceptorsEGFR–Agoodtargetforlungcancer(nonsmallcell)Highlevelofreceptorexpressioncomparedwithhealthytissue.EGFR-Keyroleintumourcellgrowth&function.EGFRinhibitioncaninhibitdownstreamactivity.EGFRinhibitorshavenoseveretoxicity.RationaleforEGFRInhibitorsinHead&NeckcancerEGFRexpressedin90%ofhead&neckcancers.EGFRoverexpressionassociatedwithdecreasedsurvival.IncreasedEGFRexpressionisanearlyeventincarcinogenesis&evenpresentinpremalignantlesions.InhibitionofEGFR–TKslowsthegrowthofxenografttumourmodelsofhead&neck.TKTKTKTKStrategiestoinhibitEGFRsignaling----EGFRtyrosinekinaseinhibitorsAnti-EGFRmAbsAnti-ligandmAbsBispecificAbsImmuneeffectorcellATPDrugsAvailableGefitinibErlotinibHighlyselective,potent&reversibleEGFRTyrosineKinaseInhibitorCetuximab–MonoclonalAntiEGFRantibodyH447MDX210BispecificAntiEGFRantibodylinkedtoAntiCD64IndicationsMonotherapyinadvancedstageofNSCLCGefitinib&Erlotinib:Gefitinib250mgO.D.oralErlotinib150mgO.D.oralCetuximab400mg/m2i.v.→200mg/m2i.v.wklyCetuximabMetastaticcolorectalcancerwith/withoutIrinotecanDoseSideEffectsSkinrashDiarrhoea(EGFR–TKIs)Fever(EGFR–mAb)Interstitiallungdisease–1%(onlyforGefitinib)Discontinuationratesduetoadverseeffectsareverylowunlikechemotherapy.DrugInteractionsEGFR–TKInhibitorsmetabolisedbyCYP3A4.Inhibitors/inducersofCYP3A4canalterdruglevels.WarfarininteractionshaveoccurredinclinicaltrialsofGefitinib.ConcomitantadministrationwithwarfarinrequiresmonitoringofPT,INR.AdvantagesofEGFRInhibitorsOrallyeffectiveBetterqualityoflife.Canbeusedasmonotherapy.Noneedforpremedicationordosemonitoring.Nohematologicaltoxicity.Potentialforlongtermtreatment.ReducedresistancetoradiationorhormonetherapyCurrentStatusGefitinibFDAApprovedonMay,2003forLungcancer-NSC(AcceleratedApprovalProgramme)ErlotinibFDAApprovedonNov,2004forLungcancer–NonSmallCell(AAP)CetuximabFDAApprovedonFeb,2004foradvancedcolorectalcancerClinicalTrialsParameterIDEALIIDEALIIDesignRandomizeddoubleblindParallelGroup,multicenterRandomizeddoubleblindparallelgroup,multicenterProtocolMonotherapyMonotherapyNofpatients209216CancerAdvancedNSCLC;1-2priorChemotherapycyclesAdvancedNSCLC;2priorChemotherapycyclesDose/regimen250or500mg/day250or500mg/dayAdverseeffectsGI,RashGI,RashActivityCR/PR18%&19%,CR/PR/SD54%&51OS7.6&7.9mnthsat250&500mg/dCR/PR12%&9%,CR/PR/SD42%&36%;OS6.5&5.9mnthsat250&500mg/dGefitinibPhaseIITrialsParameterINTACTIINTACTIIDesignRandomizeddoubleblindPlacebocont.,multicenterRandomizeddoubleblindplacebocont.,multicenterProtocolCombination–gemcitabine&cisplatinCombination-Carboplatin&PaclitaxelNofpatients10931037CancerAdv.NSCLCChemotherapynaïvestageIII/IVAdv.NSCLC;ChemotherapynaïvestageIII/IVDose/regimenStd.chemoplus250or500mg/dayStd.chemoplus250or500mg/dayA