CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival

Glioblastoma is the most prevalent and aggressive malignant tumor of the central nervous system. With a median overall survival of only one year, glioblastoma patients have a particularly poor prognosis, highlighting a clear need for novel therapeutic strategies to target this disease. Transcriptional cyclin-dependent kinases (tCDK), which phosphorylate key residues of RNA polymerase II (RNAPII) c-terminal domain (CTD), play a major role in sustaining aberrant transcriptional programs that are key to development and maintenance of cancer cells. Here, we show that either pharmacological inhibition or genetic ablation of the tCDKs, CDK12 and CDK13, markedly reduces both the proliferation and migratory capacity of glioma cells and patient-derived organoids. Using a xenograft mouse model, we demonstrate that CDK12/13 inhibition not only reduces glioma growthin vivo. Mechanistically, inhibition of CDK12/CDK13 leads to a genome-wide abrogation of RNAPII CTD phosphorylation, which in turn disrupts transcription and cell cycle progression in glioma cells. In summary, the results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for glioblastoma.