CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality [RNA-Seq]
Biallelic 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 screening 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 ability 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 study of prostate cancer.  Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC. Overall design: To investigate role of CDK12 in prostate cancer development, we established Cdk12 KO vs WT mouse prostate organoids from GEMM model We then performed gene expression analysis using RNA-seq of Cdk12 KO vs WT organoid line We also knockout sgP53 using CRISPR technology in Cdk12 KO vs WT organoids and compaired gene expression profiling from 4 different organoid lines (WT-sgNT, WT-sgP53, CDK12 KO-sgNT, CDK12 KO-sgP53)