Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.[2017][Nature][10.1038_nature22341]

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1、ARTICLEdoi:10.1038/nature22341ExosomesfacilitatetherapeutictargetingofoncogenicKRASinpancreaticcancerSushrutKamerkar1,ValerieS.LeBleu1,HikaruSugimoto1,SujuanYang1,CarolinaF.Ruivo2,SoniaA.Melo1,2,J.JackLee3&RaghuKalluri1ThemutantformoftheGTPaseKRASisakeydriverofpancr

2、eaticcancerbutremainsachallengingtherapeutictarget.Exosomesareextracellularvesiclesgeneratedbyallcells,andarenaturallypresentintheblood.Hereweshowthatenhancedretentionofexosomes,comparedtoliposomes,inthecirculationofmiceislikelyduetoCD47-mediatedprotectionofexosomes

3、fromphagocytosisbymonocytesandmacrophages.Exosomesderivedfromnormalfibroblast-likemesenchymalcellswereengineeredtocarryshortinterferingRNAorshorthairpinRNAspecifictooncogenicKrasG12D,acommonmutationinpancreaticcancer.Comparedtoliposomes,theengineeredexosomes(knownas

4、iExosomes)targetoncogenicKRASwithanenhancedefficacythatisdependentonCD47,andisfacilitatedbymacropinocytosis.TreatmentwithiExosomessuppressedcancerinmultiplemousemodelsofpancreaticcancerandsignificantlyincreasedoverallsurvival.Ourresultsdemonstrateanapproachfordirect

5、andspecifictargetingofoncogenicKRASintumoursusingiExosomes.Pancreaticductaladenocarcinoma(PDAC)isinurgentneedofeffec-enhancingspecificitytopancreaticcancercells,respectively.Suchprop-tivenewtherapies1.MutationsintheGTPaseKRASarecommonlyertiesofexosomesenhancedtheira

6、bilitytodeliverRNAitospecificallyencounteredinPDAC2andthesedriveinitiation,progressionandtargetoncogenicKRASinpancreatictumours,andtheuseofexosomesmetastasis3,4.DampeningoncogenicKrasusinggeneticmanipula-assingletargetedagentssignificantlyimprovedtheoverallsurvivalo

7、ftioninmiceinhibitstumourprogressiondespitethepresenceofotherallmousemodelsofPDACtested.geneticdefects5.AdirectandspecifictargetingofRASfamilyproteinshashoweverbeenelusive6.CD47suppressesexosomeclearancebymonocytesRNAinterference(RNAi)-basedapproachestotargetwild-ty

8、peKrasExosomeswerepurifiedfromthesupernatantofnormalhumanfore-ordownstreameffectorsusingnanoparticlesshowedaneffectontumourskinfibroblast(