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1、ANTICANCERRESEARCH27:1879-1882(2007)AcquiredResistanceofPulmonaryAdenocarcinomatoInitiallySuccessfulTargetedTherapyduetoEGFRMutationT790MD.JANCARIKOVA1,M.PESEK1,L.BENESOVA3,O.TOPOLCAN2,L.HOLUBECJr.2andM.MINARIK31DepartmentofTuberculosisandRespiratoryDiseases,2SecondDepartmen
2、tofInternalMedicine,CharlesUniversity,MedicalSchoolandTeachingHospitalPlzen;3LaboratoryforMolecularGeneticsandOncology,GenomacInternational,Prague,CzechRepublicAbstract.Accordingtopreviousreportsintheliterature,thesignalsthroughtheinhibitionoftheepidermalgrowthfactorT790Mmut
3、ationindicatesanacquiredresistancetotyrosinereceptor(EGFR)(1,2).TheEGFRgeneproduct,atyrosinekinaseinhibitors.Theinitialpositiveeffectofcombinationkinase,hasanimportantfunctioninthetransductionofchemotherapywitherlotinibasthefirstlineoftreatmentgrowthsignalsbyphosphorylationo
4、fothercascadeproteins.correlateswithseveralpositivepredictorsincludingthetypeofTheenzymaticreactiontakesplaceataspecificEGFRsite,carcinoma,non-smokingstatus,occurrenceofrashandthetheATP-bindingpocket,whichiscodedwithintherangeofpresenceofexon19EGFRgenemutation.Thecaseofaexon
5、s18through21.BlockingoftheATPpocketbylow32-year-old,non-smokerwithnon-contributoryhistorypatient,molecularagentsdeactivatestheEGFRfunctionandstopswhowasdiagnosedwithadenocarcinomaintheleftlungtransductionofthegrowthsignal.ThisprincipleisutilizedbyT4N0M0stageIIIBisreported.Th
6、epatientunderwent6cyclestwoclinicallyapprovedlow-moleculartyrosinekinaseofchemotherapywitherlotinib,gemcitabineandcisplatin,inhibitors:gefitinib(IRESSA®)anderlotinib(TARCEVA®).followedbycompleteremission.FifteenmonthsafterTyrosinekinaseactivityistightlyregulatedinnormalcells
7、,commencingtherapy,diseaserecurredoversubsequenttherapybutdysregulatedduetomutationinsometypesofcancer,witherlotinibandthengefitinib.Duringthattime,boneandincludinglungcancer.Malignantcellsbecomedependentoncerebralmetastaseswithpericardialeffusionweredetected.Thegrowthsignal
8、sfromthemutanttyrosinekinases(3,4).Inmidpatientdied7monthslater.Geneticexam