1AlternativeSplicinginProstateCancerA.Paschalisab,A.Sharpab,J.C.Weltia,ANeeba,GaneshV.Rajcd,JunLuoe,StephenR.PlymatefandJ.S.deBonoab^.aTheInstituteforCancerResearch,London,UKbTheRoyalMarsdenNHSFoundationTrust,London,UKcDepartmentofUrology,UniversityofTexasSouthwesternMedicalCenter,Dallas,TexasdDepartmentofPharmacology,UniversityofTexasSouthwesternMedicalCenter,Dallas,TexaseDepartmentofUrology,JohnsHopkinsUniversity,Baltimore,MDfDepartmentofMedicine,UniversityofWashingtonSchoolofMedicineandVAPSHCS-GRECC,Seattle,WA^Correspondingauthor^JohannS.deBono,M.D.Ph.D.,TheInstituteofCancerResearch,TheRoyalMarsdenNHSFoundationTrust,LondonSM25NG,UK;Tel:44-20-8722-4028;Johann.de-Bono@icr.ac.ukRunningHead:AlternativeSplicinginprostatecancerKeywords:Androgenreceptor,androgenreceptorsplicevariants,spliceosome,alternativesplicing,prostatecancer,castrationresistantprostatecancer,radio-resistanceNumberofFigures:4NumberofTables:1Abstractwordcount:220Wordcount(excludingFigurelegends,TablesandReferences):6738References:1352AbstractProstatecancerkillsonemanevery45minutes.Androgenreceptorsplicevariants(AR-V)appeartoplayacriticalroleintheprogressionofmetastaticprostatecancer.AR-VsaretruncatedARisoformsthatlacktheARligandbindingdomainandremainconstitutivelyactiveintheabsenceofandrogen,promotingcancercellproliferationthroughaberrantactivationofAR-mediatedcellsurvivalpathways.Consequently,AR-Vshavebeenproposedtocontributetonotonlytreatmentresistanceagainstanti-androgentherapies,butalsoradio-resistanceinpatientsreceivingcombinationandrogendeprivationtherapyandradiationbybolsteringDNArepairmechanisms.AR-Vssuchasandrogenreceptorvariant7(AR-V7)havebeenassociatedwithworseclinicaloutcomes,howeverattemptstospecificallyinhibitorpreventformationofAR-Vshavetodatebeenunsuccessful.Thus,noveltherapeuticstrategiesaredesperatelyneededtoaddresstheactionofAR-Vsthatdrivelethalformsofprostatecancer.Disruptionofalternativesplicingthroughmodulationofthespliceosomeisonesuchpotentialtherapeuticavenue,howeverourunde...
