platinum-basedchemotherapy.Varioustargetedtherapiesarebeingclinicallyandpreclinicallytestedforbladdercancermanagement.Metastaticbladdercancerhasbeenassociatedwithlossofcellcyclecontrol.TCGAanalysisalsorevealedthatTP53mutationsweremutuallyexclusiveintheirrelationshipwithoverexpressionandamplificationofMDM2,therebyresultingininactivationofp53functionin76%ofsamples.DefectsintheRBpathwayareanothermajormechanismsbywhichcellcyclecontrolislostinmetastaticbladdercancer.TheCDK4/6complexcombineswithcyclinD1toinhibitRBactivity.TherapeutictargetingofthiscompleximprovesoutcomeinERpositiveadvancedbreastcancer.