REVIEWARTICLEOPENPIMkinaseinhibition:co-targetedtherapeuticapproachesinprostatecancerSabinaLuszczak1,ChristopherKumar1,VigneshKrishnaSathyadevan1,BenjaminS.Simpson1,KathyA.Gately2,HayleyC.Whitaker1andSusanHeavey1PIMkinaseshavebeenshowntoplayaroleinprostatecancerdevelopmentandprogression,aswellasinsomeofthehallmarksofcancer,especiallyproliferationandapoptosis.Theirupregulationinprostatecancerhasbeencorrelatedwithdecreasedpatientoverallsurvivalandtherapyresistance.InitialeffortstoinhibitPIMwithmonotherapieshavebeenhamperedbycompensatoryupregulationofotherpathwaysanddrugtoxicity,andassuch,ithasbeensuggestedthatco-targetingPIMwithothertreatmentapproachesmaypermitlowerdosesandbeamoreviableoptionintheclinic.Here,wepresenttherationaleandbasisforco-targetingPIMwithinhibitorsofPI3K/mTOR/AKT,JAK/STAT,MYC,stemness,andRNAPolymeraseItranscription,alongwithothertherapies,includingandrogendeprivation,radiotherapy,chemotherapy,andimmunotherapy.Suchcombinedapproachescouldpotentiallybeusedasneoadjuvanttherapies,limitingthedevelopmentofresistancetotreatmentsorsensitizingcellstoothertherapeutics.TodeterminewhichdrugsshouldbecombinedwithPIMinhibitorsforeachpatient,itwillbekeytodevelopcompaniondiagnosticsthatpredictresponsetoeachco-targetedoption,hopefullyprovidingapersonalizedmedicinepathwayforsubsetsofprostatecancerpatientsinthefuture.SignalTransductionandTargetedTherapy(2020)5:7;https://doi.org/10.1038/s41392-020-0109-yINTRODUCTIONProstatecancer(PCa)isoneofthemostcommoncancersamongmen,with1.1millioncasesperyearworldwide.1Ascurrenttreatments,2,3includingsurgery,radiotherapy,chemotherapy,andhormonetherapy,resultinseveresideeffects,4thedevelopmentofnewtargetedtherapieswithlowertoxicitycouldsignificantlyimprovepatientqualityoflifeandpotentiallyextendlife.Moreover,neoadjuvanttherapeuticseffectiveatreducingtumorvolumecouldpotentiallyallowbetterpreservationoferectilefunctionandurinarycontinenceinradicalprostatectomypatients.2,5TumorigenesisinPCaisoftendependentonaberrationsinoneofthekeysi...
