Human genome analyses have revealed that increasing gene copy number alteration is a driving force of incurable cancer of the prostate (CaP). Since most of the affected genes are hidden within large amplifications or deletions, there is a need for fast and faithful validation of drivers. However, classic genetic CaP engineering in mouse makes this a daunting task because generation, breeding based combination of alterations and non-invasive monitoring of disease are too time consuming and costly. To address the unmet need, we recently developed RapidCaP mice, which endogenously recreate human PTEN-mutant metastatic CaP based on Cre/Luciferase expressing viral infection, that is guided to Pten(loxP)/Trp53(loxP) prostate. Here we use a sensitized, non-metastatic Pten/Trp53-mutant RapidCaP system for functional validation of human metastasis drivers in a much accelerated time frame of only 3-4months. We used in vivo RNAi to target three candidate tumor suppressor genes FOXP1, RYBP and SHQ1, which reside in a frequent deletion on chromosome 3p and show that Shq1 cooperates with Pten and p53 to suppress metastasis. Our results thus demonstrate that the RapidCaP system forms a much needed platform for in vivo screening and validation of genes that drive endogenous lethal CaP.