GSE254388 CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality [RNA-Seq]

Contributors : Jean C Tien ; Yuping Zhang ; Yu Chang ; Yunhui Cheng ; Rahul Mannan ; Palak Shan ; Xiaoming Wang ; Sanjana Eyunni ; Caleb Cheng ; Brian Magnuson ; Lanbo Xiao ; Marcin Cieslik ; Abhijit Parolia ; Yi Bao ; Shuqin Li ; Alice Xu ; Fengyun Su ; Xuhong Cao ; Yi-Mi Wu ; Dan Robinson ; George Wang ; Ke Ding ; Arul M ChinnaiyanSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusBiallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development —either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR sc reening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and abil ity to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the stud...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research