insulin like growth factor i receptor signalling and acquired resistance to gefitinib (zd1839, iressa) in human breast and prostate cancer cells外语英文电子书

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1、Endocrine-RelatedCancer(2004)11793–814Insulin-likegrowthfactor-Ireceptorsignallingandacquiredresistancetogefitinib(ZD1839;Iressa)inhumanbreastandprostatecancercells1HEJones,LGoddard,JMWGee,SHiscox,MRubini,DBarrow,2JMKnowlden,SWilliams,AEWakelingandRINicholsonTenovusCentreforCancerResearch,WelshSchoo

2、lofPharmacy,RedwoodBuilding,UniversityofCardiff,KingEdwardVIIAvenue,CardiffCF103XF,UK1DipartimentodiMedicinaSperimentaleeDiagnostica,UniversitadiFerrara,Ferrara,Italy2AstraZenecaPharmaceuticals,Mereside,AlderleyPark,Macclesfield,Cheshire,UK(RequestsforoffprintsshouldbeaddressedtoHEJones;Email:jonesh

3、e1@cardiff.ac.uk)AbstractDenovoandacquiredresistancetotheanti-tumourdruggefitinib(ZD1839;Iressa),aspecificepidermalgrowthfactorreceptor(EGFR)tyrosinekinaseinhibitor(TKI)hasbeenreported.WehavedeterminedwhethersignallingthroughtheIGF-Ireceptor(IGF-1R)pathwayplaysaroleinthegefitinib-acquiredresistancephe

4、notype.ContinuousexposureofEGFR-positiveMCF-7-derivedtamoxifenresistantbreastcancercells(TAM-R)to1mMgefitinibresultedinasustainedgrowthinhibition(90%)for4monthsbeforethesurvivingcellsresumedproliferation.Astablegefitinib-resistantsubline(TAM/TKI-R)wasestablishedafterafurther2monthsandthisshowednodete

5、ctablebasalphosphorylatedEGFRactivity.ComparedwiththeparentalTAM-Rcells,theTAM/TKI-Rcellsdemonstrated(a)elevatedlevelsofactivatedIGF-1R,AKTandproteinkinaseC(PKC)d,(b)anincreasedsensitivitytogrowthinhibitionbytheIGF-1RTKIAG1024and(c)anincreasedmigratorycapacitythatwasreducedbyAG1024treatment.Similar

6、ly,theEGFR-positiveandrogen-independenthumanprostatecancercelllineDU145wasalsocontinuouslychallengedwith1mMgefitiniband,althoughsubstantialgrowthinhibition(60%)wasseeninitially,agefitinib-resistantvariant(DU145/TKI-R)developedafter3months.Liketheirbreastcancercounterparts,theDU145/TKI-Rcellsshowedinc

7、reasesinthelevelsofcomponentsoftheIGF-1RsignallingpathwayandanelevatedsensitivitytogrowthinhibitionbyAG1024comparedwiththeparentDU145cellline.Additionally,DU145/TKI-Rcellmigrationwasalsodecreasedbythisinhib