CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13
Jean C. Tien, Jie Luo, Yu Chang, Yuping Zhang, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Somnath Mahapatra, Palak Shah, Xiaoming Wang, Abigail J. Todd, Sanjana Eyunni, Caleb Cheng, Ryan J. Rebernick, Lanbo Xiao, Yi Bao, James Neiswender, Rachel Brough, Stephen J. Pettitt, Xuhong Cao, Stephanie J. Miner, Licheng Zhou, Yi‐Mi Wu, Estefanía Labanca, Yuzhuo Wang, Abhijit Parolia, Marcin Cieślik, Dan R. Robinson, Zhen Wang, Felix Y. Feng, Jonathan Chou, Christopher J. Lord, Ke Ding, Arul M. Chinnaiyan
Abstract
Biallelic loss of cyclin-dependent kinase 12 ( CDK12 ) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12 / Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten -null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12 / Trp53 -null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12 -mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12- mutant mCRPC. • Cdk12 ablation induces preneoplastic prostate lesions with T cell infiltration • Cdk12 loss mediates genomic instability through transcription-replication conflicts • Cdk12 / Trp53 knockout in murine allografts sensitizes to immune checkpoint blockade • CDK12 loss sensitizes paralog-based synthetic lethality via targeting CDK13 Tien et al. employ mouse models to define Cdk12 as a bona fide prostate cancer tumor suppressor gene. Cdk12 loss promotes transcription-replication conflicts, inducing DNA damage. Murine and human prostate tumors with inactive CDK12 exhibit paralog-based synthetic lethality upon pharmacologic targeting of CDK13—a strategy with potential clinical application.