CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13
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.
Authors
- Ke Ding (ORCID: https://orcid.org/0000-0001-9016-812X)
- Licheng Zhou (ORCID: https://orcid.org/0000-0002-8145-5124)
- Arul M. Chinnaiyan (ORCID: https://orcid.org/0000-0001-9282-3415)
- Jean C. Tien (ORCID: https://orcid.org/0000-0002-2684-4450)
- Jianzhang Yang
- Rachel Brough (ORCID: https://orcid.org/0000-0002-1862-7130)
- Jonathan Chou (ORCID: https://orcid.org/0000-0003-1258-0391)
- Felix Yi-Chung Feng (ORCID: https://orcid.org/0000-0002-0963-7687)
- Somnath Mahapatra (ORCID: https://orcid.org/0000-0001-9490-6353)
- Sanjana Eyunni (ORCID: https://orcid.org/0009-0006-5101-6506)
- Xuhong Cao (ORCID: https://orcid.org/0000-0002-2455-3086)
- James Neiswender (ORCID: https://orcid.org/0000-0003-4135-6479)
- Ryan J. Rebernick (ORCID: https://orcid.org/0000-0002-5532-581X)
- Abhijit Parolia (ORCID: https://orcid.org/0000-0003-0238-221X)
- Marcin Cieślik (ORCID: https://orcid.org/0000-0002-5467-1040)
- Rahul Mannan (ORCID: https://orcid.org/0000-0002-6642-0468)
- Estefanía Labanca (ORCID: https://orcid.org/0000-0003-3201-7790)
- Stephanie J. Miner (ORCID: https://orcid.org/0009-0005-6680-900X)
- Dan R. Robinson (ORCID: https://orcid.org/0000-0002-2337-7439)
- Stephen J. Pettitt (ORCID: https://orcid.org/0000-0003-3313-3857)
- Christopher J. Lord (ORCID: https://orcid.org/0000-0002-3226-0515)
- Yi‐Mi Wu (ORCID: https://orcid.org/0000-0002-3789-4445)
- Xiaoming Wang (ORCID: https://orcid.org/0000-0003-0679-9768)
- Zhen Wang
- Yuping Zhang (ORCID: https://orcid.org/0000-0003-1055-2071)
- Yu Chang (ORCID: https://orcid.org/0009-0009-0970-7794)
- Yuzhuo Z. Wang (ORCID: https://orcid.org/0000-0002-9749-8591)
- Xiaoju Wang (ORCID: https://orcid.org/0000-0002-1800-4902)
- Yunhui Cheng
- Caleb Cheng (ORCID: https://orcid.org/0000-0003-1872-2661)
- Lanbo Xiao (ORCID: https://orcid.org/0000-0002-1614-8806)
- Palak Shah
- Abigail J. Todd (ORCID: https://orcid.org/0009-0002-3379-2158)
- Jie Luo
- Yi Bao (ORCID: https://orcid.org/0000-0002-6738-0963)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- University of British Columbia (CA)
- Institute of Cancer Research (GB)
- Jinan University (CN)
- University of California, San Francisco (US)
- Chinese Academy of Sciences (CN)
- University of Michigan (US)
- Breast Cancer Now (GB)
- Vancouver General Hospital (CA)
- Shanghai Institute of Organic Chemistry (CN)
- Michigan Medicine (US)
- Michigan Center for Translational Pathology (US)
- Ministry of Education (TH)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101758
- Citations
- 24
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 6.78
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Cancer Research UK
- National Natural Science Foundation of China
- University of Texas MD Anderson Cancer Center
- National Cancer Institute