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CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with

Jean Ching-Yi Tien1, Jie Luo1, Yu Chang1

  • 1Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Cell Reports. Medicine
|October 5, 2024
PubMed

Insights

Loss of cyclin-dependent kinase 12 (CDK12) in prostate cancer promotes tumor development and genomic instability. CDK12-mutant cancers show sensitivity to CDK13 inhibition, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Biallelic loss of cyclin-dependent kinase 12 (CDK12) identifies a metastatic castration-resistant prostate cancer (mCRPC) subtype.
  • The role of CDK12 loss in prostate cancer (PCa) pathogenesis and its implications for treatment remain incompletely understood.

Purpose of the Study:

  • To investigate whether CDK12 loss drives PCa development or creates therapeutic vulnerabilities.
  • To elucidate the mechanistic link between CDK12 inactivation and genomic instability.
  • To identify potential therapeutic strategies for CDK12-mutant mCRPC.

Main Methods:

  • Murine prostate epithelium Cdk12 ablation models.
  • Allograft-based CRISPR screening.
  • Prostate-derived organoid culture.
  • Syngeneic mouse models.
  • Analysis of patient-derived xenografts.

Main Results:

  • Cdk12 ablation in mice induced preneoplastic lesions and lymphocytic infiltration.
  • Cdk12 loss associated with Trp53 inactivation and inversely with Pten inactivation.
  • Concurrent Cdk12/Trp53 ablation enhanced organoid proliferation, while Cdk12 knockout in Pten-null mice suppressed tumor growth.
  • Cdk12/Trp53-null allografts displayed luminal morphology and responded to immune checkpoint blockade.
  • CDK12 inactivation caused genomic instability via transcription-replication conflicts.
  • CDK12-mutant organoids and xenografts were sensitive to CDK13 inhibition/degradation.

Conclusions:

  • CDK12 acts as a tumor suppressor in prostate cancer.
  • CDK12 inactivation leads to genomic instability through transcription-replication conflicts.
  • Targeting CDK13 presents a promising therapeutic avenue for CDK12-mutant mCRPC.
Keywords:
CDK12CDK13Cdk12 knockoutR-loopsparalog-based synthetic lethalityprostate cancertranscription-replication conflicts

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