Faculty, Staff and Student Publications

Publication Date

10-15-2024

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2024.101758

PMID

39368479

PMCID

PMC11513839

PubMedCentral® Posted Date

10-4-2024

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Male, Animals, Humans, Cyclin-Dependent Kinases, Mice, Synthetic Lethal Mutations, Prostatic Neoplasms, Tumor Suppressor Protein p53, Disease Progression, PTEN Phosphohydrolase, Genomic Instability, Transcription, Genetic, Organoids, Prostatic Neoplasms, Castration-Resistant, Cell Proliferation, DNA Replication, Mice, Knockout, Cell Line, Tumor, Mice, Inbred C57BL, CDC2 Protein Kinase, CDK12, CDK13, prostate cancer, Cdk12 knockout, transcription-replication conflicts, R-loops, paralog-based synthetic lethality

Published Open-Access

yes

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