ArticleCell reports. Medicine2024
CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13.
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Article in Cell reports. Medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31citing papers in PubMed
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Who cites it
31 citing papers in PubMed.
- Gemogenovatucel-T Advantage in Clonal Tumor Mutation Burden-High Ovarian Cancer.JCO precision oncology · 2026Trial
- RNA polymerase II phosphorylation dynamics: from molecular mechanisms to human disease.RNA biology · 2026Review
- CDK12/13 inhibition overcomes platinum resistance by impairing RNA metabolism.Signal transduction and targeted therapy · 2026Article
- High-Content CRISPR Screening: Methods and Applications.MedComm · 2026Review
- CDK12/13 Inhibition Induces DNA Hypomethylation and Sensitizes Cancer Cells to Compounds Targeting DNA-PK.Journal of cellular and molecular medicine · 2026Article
- A ligandable PNT domain establishes ERG as a directly targetable oncogenic driver in prostate cancer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Exploring Genetic Contributions to Prostate Cancer Risk in an Asian Population-Based Study.Cancer medicine · 2026Article
- Inhibition of cyclin-dependent kinases 12/13 using CT7439 as a treatment for colorectal cancer with CDK12 upregulation.Molecular oncology · 2026Article
- Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review).International journal of oncology · 2026Review
- Polymerase face-off: emerging concepts in transcription-replication coordination.EMBO reports · 2026Review
- Rewiring Oncogenic Transcriptional Complexes with Domain-ALTeration Chimeras (DALTACs) in Prostate Cancer.bioRxiv : the preprint server for biology · 2026Article
- Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage.Journal of cellular and molecular medicine · 2026Article
- The Emerging Role of Transcription-Associated Cyclin-Dependent Kinases in Gastrointestinal Tumors.Cancers · 2026Review
- CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy.Cell proliferation · 2026Article
- Recent advances and future prospects of immunotherapeutic approaches in prostate cancer.Journal of translational medicine · 2026Review
- CDK12 and CDK13 in oncology: from RNA regulation to therapeutic targeting.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Patient-derived prostate cancer organoids: model development, therapeutic applications, and challenges for precision oncology.Frontiers in oncology · 2026Review
- Article
- Complex Relationships Between Homologous Recombination Deficiency (HRD) Score and Mutational Status of Homologous Recombination Repair (HRR) Genes in Prostate Carcinomas.International journal of molecular sciences · 2025Article
- Molecular Characterization of Seminoma Utilizing the AACR Project GENIE: A Retrospective Observational Study.Cancers · 2025Article
Corrections and comments
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Authors and funding
35 authors.
Jean Ching-Yi TienMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jie LuoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yu ChangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yuping ZhangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yunhui ChengMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Xiaoju WangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jianzhang YangState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, People's Republic of China.
Rahul MannanMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Somnath MahapatraMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Palak ShahMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Xiao-Ming WangMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Abigail J ToddMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Sanjana EyunniMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Caleb ChengMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Ryan J RebernickMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Lanbo XiaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yi BaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
James NeiswenderThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, UK.
Rachel BroughThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, UK.
Stephen J PettittThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, UK.
Xuhong CaoMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Stephanie J MinerMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Licheng ZhouState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, People's Republic of China.
Yi-Mi WuMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Estefania LabancaDepartment of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancer, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yuzhuo WangVancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
Abhijit ParoliaMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Marcin CieslikMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Dan R RobinsonMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Zhen WangState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, People's Republic of China.
Felix Y FengDepartments of Radiation Oncology and Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Jonathan ChouHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Christopher J LordThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, UK.
Ke DingState Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People's Republic of China. Electronic address: dingk@sioc.ac.cn.
Arul M ChinnaiyanMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA. Electronic address: arul@med.umich.edu.
Funding
MICHIGAN MEDICAL SCIENTIST TRAINING PROGRAMT32GM007863 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, KATHLEEN L. · 1985 to 2024
$38.3MTissue/InformaticsP50CA186786 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Ganesh S Palapattu · 2014 to 2026
$27.6MExploring Precision Oncology: From Gene Fusions to lncRNAsR35CA231996 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHINNAIYAN, ARUL M · 2018 to 2024
$6.4MMichigan-VUMC Biomarker Characterization CenterU2CCA271854 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jeffrey John Tosoian · 2022 to 2026
$5.4MNCI NIH HHS P50 CA186786NCI NIH HHS R35 CA231996NCI NIH HHS U2C CA271854NIGMS NIH HHS T32 GM007863
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.
Indexed as
Cyclin-Dependent KinasesProstatic NeoplasmsSynthetic Lethal MutationsAnimalsCDC2 Protein KinaseCell Line, TumorCell ProliferationDisease ProgressionDNA ReplicationGenomic InstabilityHumansMaleMiceMice, Inbred C57BLMice, KnockoutOrganoidsCDC2 Protein KinaseCDK12 protein, humanCDK13 protein, humanCyclin-Dependent KinasesPTEN PhosphohydrolaseTumor Suppressor Protein p53CDK12Cdk12 knockoutCDK13paralog-based synthetic lethalityprostate cancerR-loopstranscription-replication conflicts
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.