Gefitinib Induces Epidermal Growth Factor Receptor Dimers Which Alters the Interaction Characteristics with 125I-EGF 英文参考文献.docVIP

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Gefitinib Induces Epidermal Growth Factor Receptor Dimers Which Alters the Interaction Characteristics with 125I-EGF 英文参考文献.doc

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Gefitinib Induces Epidermal Growth Factor Receptor Dimers Which Alters the Interaction Characteristics with 125I-EGF 英文参考文献

GefitinibInducesEpidermalGrowthFactorReceptor DimersWhichAlterstheInteractionCharacteristicswith 125I-EGF HannaBjo¨rkelund1,2*,LarsGedda1,PavelBarta3,MagnusMalmqvist1,2,4,KarlAndersson1,2 1BiomedicalRadiationSciences,DepartmentofRadiology,OncologyandRadiationScience,UppsalaUniversity,Uppsala,Sweden,2RidgeviewInstrumentsAB,Uppsala, Sweden,3DepartmentofPharmacologyandToxicology,FacultyofPharmacyinHradecKralove,CharlesUniversityinPrague,Prague,CzechRepublic,4BioventiaAB, Uppsala,Sweden Abstract The tyrosine kinase inhibitor gefitinib inhibits growth in some tumor types by targeting the epidermal growth factor receptor(EGFR).PreviousstudiesshowthattheaffinityoftheEGF-EGFRinteractionvariesbetweenhostingcellline,and that gefitinib increases the affinity for some cell lines. In this paper, we investigate possible mechanisms behind these observations.Real-timeinteractionanalysisinLigandTracerHGreyrevealedthattheHER2dimerizationpreventingantibody pertuzumab clearly modified the binding of 125I-EGF to EGFR on HER2 overexpressing SKOV3 cells in the presence of gefitinib. Pertuzumab did not affect the binding on A431 cells, which express low levels of HER2. Cross-linking measurementsshowedthatgefitinibincreasedtheamountofEGFRdimers3.0–3.8timesinA431cellsintheabsenceof EGF. In EGF stimulated SKOV3 cells the amount of EGFR dimers increased 1.8–2.2 times by gefitinib, but this effect was cancelledbypertuzumab.GefitinibtreatmentdidnotalterthenumberofEGFRorHER2expressedintumorcelllinesA431, U343,SKOV3andSKBR3.Real-timebindingtraceswerefurtheranalyzedinanoveltool,InteractionMap,whichdeciphered thedifferentcomponentsofthemeasuredinteractionandsupportsEGFbindingtomultiplebindingsites.EGFRandHER2 expressionaffectthelevelsofEGFRmonomers,homodimersandheterodimersandEGFbindstothevariousmonomeric/ dimericformsofEGFRwithuniquebindingproperties.Takentogether,weconcludethatdimerizationexplainsthevarying affinityofEGF–EGFRindifferentcells,andweproposethatgefitinibinducesEGFRdimmers,whichalter