EGFR tyrosine kinase inhibitors

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1、NIHPublicAccessAuthorManuscriptOncogene.Authormanuscript;availableinPMC2010April5.NIH-PAAuthorManuscriptPublishedinfinaleditedformas:NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptOncogene.2009August;28(Suppl1):S24±S31.doi:10.1038/onc.2009.198.Activatingandresistancemuta

2、tionsofEGFRinnon-small-celllungcancer:roleinclinicalresponsetoEGFRtyrosinekinaseinhibitorsAFGazdarHamonCenterforTherapeuticOncologyResearchandDepartmentofPathology,UniversityofTexasSouthwesternMedicalCenter,Dallas,Texas,USAAbstractTheepidermalgrowthfactorreceptortyros

3、inekinaseinhibitors(EGFRTKIs),gefitinibanderlotinib,arereversiblecompetitiveinhibitorsofthetyrosinekinasedomainofEGFRthatbindtoitsadenosine-5′triphosphate-bindingsite.SomaticactivatingmutationsoftheEGFRgene,increasedgenecopynumberandcertainclinicalandpathologicalfeatu

4、reshavebeenassociatedwithdramatictumorresponsesandfavorableclinicaloutcomeswiththeseagentsinpatientswithnon-small-celllungcancer(NSCLC).ThespecifictypesofactivatingmutationsthatconfersensitivitytoEGFRTKIsarepresentinthetyrosinekinase(TK)domainoftheEGFRgene.Exon19delet

5、ionmutationsandthesingle-pointsubstitutionmutationL858Rinexon21arethemostfrequentinNSCLCandaretermed‘classical’mutations.TheNSCLCtumorsinsensitivetoEGFRTKIsincludethosedrivenbytheKRASandMEToncogenes.Mostpatientswhoinitiallyrespondtogefitinibanderlotinibeventuallybecom

6、eresistantandexperienceprogressivedisease.ThepointmutationT790Maccountsforaboutonehalfofthesecasesofacquiredresistance.Varioussecond-generationEGFRTKIsarecurrentlybeingevaluatedandmayhavethepotentialtoovercomeT790M-mediatedresistancebyvirtueoftheirirreversibleinhibiti

7、onofthereceptorTKdomain.Keywordsepidermalgrowthfactorreceptor;mutation;non-small-celllungcancer;tyrosinekinaseinhibitor;tyrosinekinaseIntroductionTheepidermalgrowthfactorreceptor(EGFR)familyofreceptortyrosinekinases(TKs),referredtoastheHERorErbBfamily,consistsoffourme

8、mbers—EGFR(HER1/ErbB1),HER2(ErbB2),HER3(ErbB3)andHER4(ErbB4)—thatregulatemanydevelopmental,metabolicandphysiologicalprocesse