Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors.

ABSTRACT:

Purpose

The cyclin-dependent kinase (CDK), CDK12, is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer characterized predominantly by frameshift, loss-of-function mutations in CDK12. This subtype exhibits aggressive clinical features.

Experimental design

Using isogenic prostate cancer models generated by CRISPR/Cas9-mediated inactivation of CDK12, we conducted a chemical library screen of ∼1,800 FDA-approved drugs. We inhibited cyclin K and CDK13 and evaluated the effects on PARP inhibitor (PARPi) sensitivity. CDK12 truncation and kinase domain mutations were expressed in cell lines to determine the effects on PARPi sensitivity. Mice bearing control and CDK12-mutant prostate tumors were treated with rucaparib. Finally, we evaluate

SUBMITTER: Chou J 

PROVIDER: S-EPMC11611633 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature