SCFSkp2/Cks1　ubiquitinates　Thr187-phosphorylated　p27　for　degradation.　Overexpression　of　Skp2　coupled　with　underexpression　of　p27　are　frequent　characteristics　of　cancer　cells.　When　the　role　of　SCFSkp2/Cksl　-　mediated　p27　ubiquitination　in　cancer　was　specifically　tested　by　p27　Thr187-to-Ala　knockin　(p27T187A　KI),　it　was　found　dispensable　for　Kras(G12D)-induced　lung　tumorigenesis　but　essential　for　Rbl-deficient　pituitary　tumorigenesis.　Here　we　identify　pRb　and　p53　doubly　deficient　(DKO)　prostate　tumorigenesis　as　a　context　in　which　p27　ubiquitination　by　SCFSkp2/Cks1　is　required　for　p27　downregulation.　p27　protein　accumulated　in　prostate　when　p27T187A　KI　mice　underwent　DKO　prostate　tumorigenesis.　p27T187A　KI　or　Skp2　knockdown　(KD)　induced　similar　degrees　of　p27　protein　accumulation　in　DKO　prostate　cells,　and　Skp2　KD　did　not　further　increase　p27　protein　in　DKO　prostate　cells　that　contained　p27T187A　KI　(AADKO　prostate　cells).　p27T187A　KI　activated　an　E2F1-p73-apoptosis　axis　in　DKO　prostate　tumorigenesis,　slowed　disease　progression　and　significantly　extended　survival.　Querying　co-occurrence　relationships　among　RB1,　TP53,　PTEN,　NKX3-1　and　MYC　in　TCGA　of　prostate　cancer　identified　co-inactivation　of　RB1　and　TP53　as　the　only　statistically　significant　co-occurrences　in　metastatic　castration-resistant　prostate　cancer　(mCRPC).　Together,　our　study　identifies　Skp2/Cks1　pocket　inhibitors　as　potential　therapeutics　for　mCRPC.　Procedures　for　establishing　mCRPC　organoid　cultures　from　contemporary　patients　were　recently　established.　An　Skp2/Cks1　pocket　inhibitor　preferentially　collapsed　DKO　prostate　tumor　organoids　over　AADKO　organoids,　which　spontaneously　disintegrated　over　time　when　DKO　prostate　tumor　organoids　grew　larger,　setting　the　stage　to　translate　mouse　model　findings　to　precision　medicine　in　the　clinic　on　the　organoid　platform.