Profiling the HER3PI3K Pathway in Breast Tumors Using Proximity-Directed Assays Identifies Correlations between Protein Complexes and Phosphoproteins 英文参考文献.docVIP

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Profiling the HER3PI3K Pathway in Breast Tumors Using Proximity-Directed Assays Identifies Correlations between Protein Complexes and Phosphoproteins 英文参考文献.doc

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Profiling the HER3PI3K Pathway in Breast Tumors Using Proximity-Directed Assays Identifies Correlations between Protein Complexes and Phosphoproteins 英文参考文献

ProfilingtheHER3/PI3KPathwayinBreastTumorsUsing Proximity-DirectedAssaysIdentifiesCorrelations betweenProteinComplexesandPhosphoproteins AliMukherjee*,YoussoufBadal,Xuan-ThaoNguyen,JohannaMiller,AhmedChenna,HasanTahir,Alicia Newton,GordonParry,StephenWilliams DepartmentofOncology,MonogramBiosciences,SouthSanFrancisco,California,UnitedStatesofAmerica Abstract Background: The identification of patients for targeted antineoplastic therapies requires accurate measurement of therapeutic targets and associated signaling complexes. HER3 signaling through heterodimerization is an important growth-promoting mechanisminseveraltumortypesandmaybeaprincipal resistancemechanism bywhichEGFRand HER2expressingtumorseludetargetedtherapies.Currentmethodsthatcanstudytheseinteractions areinadequatefor formalin-fixed,paraffin-embedded(FFPE)tumorsamples. Methodology and Principal Findings: Herein, we describe a panel of proximity-directed assays capable of measuring protein-interactions and phosphorylation in FFPE samples in the HER3/PI3K/Akt pathway and examine the capability of theseassaystoinformonthefunctionalstateofthepathway.WeusedFFPEbreastcancercelllineandtumormodelsfor thisstudy.Inbreastcancercelllinesweobservebothligand-dependentandindependentactivationofthepathwayand strongcorrelationsbetweenmeasuredactivationofkeyanalytes.WhenselectedcelllinesaretreatedwithHER2inhibitors, wenotonlyobservetheexpectedmoleculareffectsbasedonmechanismofactionknowledge,butalsonoveleffectsof HER2inhibitiononkeytargetsintheHERreceptorpathway.Significantly,inaxenograftmodelofdelayedtumorfixation, HER3 phosphorylation is unstable, while alternate measures of pathway activation, such as formation of the HER3PI3K complex is preserved. Measurements in breast tumor samples showed correlations between HER3 phosphorylation and receptorinteractions,obviatingtheneedtousephosphorylationasasurrogateforHER3activation. Significance: This assay system is capable of quantitatively measuring therapeutic