CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13.
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Embargo End Date
ICR Authors
Authors
Tien, JC-Y
Luo, J
Chang, Y
Zhang, Y
Cheng, Y
Wang, X
Yang, J
Mannan, R
Mahapatra, S
Shah, P
Wang, X-M
Todd, AJ
Eyunni, S
Cheng, C
Rebernick, RJ
Xiao, L
Bao, Y
Neiswender, J
Brough, R
Pettitt, SJ
Cao, X
Miner, SJ
Zhou, L
Wu, Y-M
Labanca, E
Wang, Y
Parolia, A
Cieslik, M
Robinson, DR
Wang, Z
Feng, FY
Chou, J
Lord, CJ
Ding, K
Chinnaiyan, AM
Luo, J
Chang, Y
Zhang, Y
Cheng, Y
Wang, X
Yang, J
Mannan, R
Mahapatra, S
Shah, P
Wang, X-M
Todd, AJ
Eyunni, S
Cheng, C
Rebernick, RJ
Xiao, L
Bao, Y
Neiswender, J
Brough, R
Pettitt, SJ
Cao, X
Miner, SJ
Zhou, L
Wu, Y-M
Labanca, E
Wang, Y
Parolia, A
Cieslik, M
Robinson, DR
Wang, Z
Feng, FY
Chou, J
Lord, CJ
Ding, K
Chinnaiyan, AM
Document Type
Journal Article
Date
2024-10-15
Date Accepted
2024-09-10
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.
Citation
Cell Reports Medicine, 2024, 5 (10), pp. 101758 -
Source Title
Cell Reports Medicine
Publisher
CELL PRESS
ISSN
2666-3791
eISSN
2666-3791
Collections
Research Team
Precision Oncology Lord