CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival
Research output: Contribution to journal › Conference abstract in journal › Research › peer-review
Background
Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant tumor of the central nervous system. With a median survival of only one year, GBM patients have a particularly poor prognosis, highlighting a clear need for novel therapeutic strategies to target this disease. Transcriptional cyclin-dependent kinases (CDK), 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.
Material and Methods
We used pharmacological inhibition and genetic ablation to study effects of CDK12/CDK13 depletion on the proliferatory and migratory capacity of GBM cells and mouse xenografts. SLAM-seq, CUT&RUN and cell cycle assays were used to study the mechanistic effects of CDK12/CDK13 depletion in GBM cells.
Results
CDK12/CDK13 depletion markedly reduced the proliferatory and migratory capacity of GBM cells, as well as in vivo growth. CDK12/CDK13 inhibition potentiated existing chemotherapeutic treatments. 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 GBM cells.
Conclusion
These results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for GBM.
Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant tumor of the central nervous system. With a median survival of only one year, GBM patients have a particularly poor prognosis, highlighting a clear need for novel therapeutic strategies to target this disease. Transcriptional cyclin-dependent kinases (CDK), 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.
Material and Methods
We used pharmacological inhibition and genetic ablation to study effects of CDK12/CDK13 depletion on the proliferatory and migratory capacity of GBM cells and mouse xenografts. SLAM-seq, CUT&RUN and cell cycle assays were used to study the mechanistic effects of CDK12/CDK13 depletion in GBM cells.
Results
CDK12/CDK13 depletion markedly reduced the proliferatory and migratory capacity of GBM cells, as well as in vivo growth. CDK12/CDK13 inhibition potentiated existing chemotherapeutic treatments. 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 GBM cells.
Conclusion
These results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for GBM.
Original language | English |
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Journal | Neuro-Oncology |
Volume | 24 |
Issue number | S2 |
Pages (from-to) | ii51 |
Number of pages | 1 |
ISSN | 1522-8517 |
DOIs | |
Publication status | Published - 2022 |
Event | 17th Meeting of the European-Association-of-Neuro-Oncology - Vienna, Austria Duration: 15 Sep 2022 → 18 Sep 2022 |
Conference
Conference | 17th Meeting of the European-Association-of-Neuro-Oncology |
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Country | Austria |
City | Vienna |
Period | 15/09/2022 → 18/09/2022 |
ID: 345409991