New EMBO Molecular Medicine paper: CDK12/CDK13 inhibition disrupts transcriptional elongation and replication fork progression in glioblastoma

Deo Prakash Pandey, leader of the "Targeting tumors of central nervous system" research group at the Department of Microbiology, and collaborators have identified a promising new therapeutic strategy for glioblastoma, the most common and aggressive malignant brain tumor in adults.

Selective vulnerability 

Glioblastoma cells, particularly glioblastoma stem cells, rely on abnormally high transcriptional activity driven by neurodevelopmental transcription factors. The study shows that these stem cells are selectively vulnerable to inhibition of the transcriptional cyclin-dependent kinases CDK12 and CDK13, while inhibition of other transcriptional kinases such as CDK7 and CDK9 results in broader, non-specific toxicity.

Unexpected effects on DNA replication

In preclinical models, CDK12/CDK13 inhibition suppresses glioblastoma stem cell and organoid proliferation, reduces invasion, and slows tumor growth in mouse xenografts. At the molecular level, blocking CDK12/CDK13 rapidly eliminates serine-2 phosphorylation on RNA polymerase II, thereby shutting down transcriptional elongation and disrupting a neurodevelopmental gene program that sustains the tumor. Unexpectedly, this also causes a marked arrest of DNA replication and replication fork progression before classical DNA damage responses are activated, in contrast to CDK9 inhibition, which accelerates fork movement. 

Therapeutic Implications

These findings reveal a tight coupling between transcriptional elongation and DNA replication in glioblastoma and highlight CDK12/CDK13 as attractive therapeutic targets, particularly if future small-molecule inhibitors can be optimized for selectivity and blood–brain barrier penetration.

Links:

Paper:
Lier S, Markusson SB, Kocijancic A, Narum M, Lund SO, Böllering B, Lipsa A, Søegaard MLC, Rein ID, Santha P, Jain P, Lång A, Lång E, Meyer N, Dutta A, Anand S, Badugu SB, Nesse GJ, Forstrøm RJ, Klungland A, Anand A, Pollard SM, Bøe SO, Rinholm JE, Frauenknecht KBM et al. (2026)
CDK12/CDK13 inhibition disrupts transcriptional elongation and replication fork progression in glioblastoma
EMBO Mol Med
DOI 10.1038/s44321-026-00393-w, PubMed 41882177

Pandey group:
OUH - Targeting tumors of central nervous system

Department of Microbiology

News articles about the findings (in Norwegian):

OUS Innsikt (www.oslo-universitetssykehus.no)
Ny lovende strategi for behandling av hjernesvulsten glioblastom

Dagens Medisin (www.dagensmedisin.no)
Nytt funn åpner for mulig ny behandlingsmåte for glioblastom