Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3KAkt and MEKERK Pathway 英文参考文献.docVIP

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Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3KAkt and MEKERK Pathway 英文参考文献.doc

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Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3KAkt and MEKERK Pathway 英文参考文献

Anti-MyelomaActivityofAktInhibitionIsLinkedtothe ActivationStatusofPI3K/AktandMEK/ERKPathway VijayRamakrishnan,TeresaKimlinger,JessicaHaug,UtkarshPainuly,LindaWellik,TimothyHalling, S.VincentRajkumar,ShajiKumar* TheDivisionsofHematology,MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica Abstract ThePI3K/Akt/mTOR signaltransductionpathwayplaysacentralrolein multiplemyeloma(MM)diseaseprogression and developmentoftherapeuticresistance.mTORC1inhibitorshaveshownlimitedefficacyintheclinic,largelyattributedtothe reactivationofAktduetorapamycininducedmTORC2activity.Here,wepresentpromisinganti-myelomaactivityofMK- 2206,anovelallostericpan-Aktinhibitor,inMMcelllinesandpatientcells.MK-2206wasabletoinducecytotoxicityand inhibitproliferationinallMMcelllinestested,albeitwithsignificantheterogeneitythatwashighlydependentonbasalpAkt levels. MK-2206 was able to inhibit proliferation of MM cells even when cultured with marrow stromal cells or tumor promotingcytokines.Theinductionofcytotoxicitywasduetoapoptosis,whichatleastpartiallywasmediatedbycaspases. MK-2206inhibitedpAktanditsdown-streamtargetsandup-regulatedpErkinMMcells.UsingMK-2206incombinationwith rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), or U0126 (MEK1/2 inhibitor), we show that Erk- mediated downstream activation of PI3K/Akt pathway results in resistance to Akt inhibition. These provide the basis for clinical evaluationofMK-2206aloneorincombinationinMMandpotentialuseofbaselinepAktandpErkasbiomarkersforpatient selection. Citation:RamakrishnanV,KimlingerT,HaugJ,PainulyU,WellikL,etal.(2012)Anti-MyelomaActivityofAktInhibitionIsLinkedtotheActivationStatusofPI3K/ AktandMEK/ERKPathway.PLoSONE7(11):e50005.doi:10.1371/journal.pone.0050005 Editor:RakeshK.Srivastava,TheUniversityofKansasMedicalCenter,UnitedStatesofAmerica ReceivedJuly10,2012;AcceptedOctober15,2012;PublishedNovember21,2012 Copyright:?2012Ramakrishnanetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,which