CDK12/13 Inhibition Induces DNA Hypomethylation and Sensitizes Cancer Cells to Compounds Targeting DNA-PK.

Inactivation of the major transcription elongation kinase, cyclin-dependent kinase 12 (CDK12), characterizes a subset of aggressive prostate cancers but it is not known how cells adapt and even benefit from this event. We show that mutations in the CDK12 gene are associated with decreased DNA methylation in patient tumours and dual inhibition of the major transcription elongation kinases, CDK12 and CDK13 decreases DNA methylation in vitro. This decrease in DNA methylation occurs particularly in the target genes of MYC (MYC Proto-Oncogene). Previously, it was established that CDK12 inhibition impairs homologous recombination, while increase in MYC activity causes DNA replication stress. We therefore hypothesized that CDK12/13 inhibition renders cells dependent on high DNA-PK activity, which is required for non-homologous end joining. Indeed, we show that genetic and pharmacological targeting of DNA-PK is toxic to cancer cells in combination with CDK12/13 inhibition. In brief, here we show that decrease in CDK12/13 activity depletes DNA methylation from MYC target genes and propose that CDK12 inactivation may serve as a biomarker of sensitivity to DNA-PK inhibitors.