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

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Standard

CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival. / Lier, S.; Rein, Kjell Arne; Lund, S.; Lång, A.; Lång, E.; Meyer, N.; Dutta, A.; Anand, S.; Nesse, G.; Johansen, R.; Klungland, A.; Rinholm, J.; Boe, S.; Anand, A.; Pollard, S.; Lerdrup, M.; Pandey, D.

In: Neuro-Oncology, Vol. 24, No. S2, 2022, p. ii51.

Research output: Contribution to journal › Conference abstract in journal › Research › peer-review

Harvard

Lier, S, Rein, KA, Lund, S, Lång, A, Lång, E, Meyer, N, Dutta, A, Anand, S, Nesse, G, Johansen, R, Klungland, A, Rinholm, J, Boe, S, Anand, A, Pollard, S, Lerdrup, M & Pandey, D 2022, 'CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival', Neuro-Oncology, vol. 24, no. S2, pp. ii51. https://doi.org/10.1093/neuonc/noac174.177

APA

Lier, S., Rein, K. A., Lund, S., Lång, A., Lång, E., Meyer, N., Dutta, A., Anand, S., Nesse, G., Johansen, R., Klungland, A., Rinholm, J., Boe, S., Anand, A., Pollard, S., Lerdrup, M., & Pandey, D. (2022). CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival. Neuro-Oncology, 24(S2), ii51. https://doi.org/10.1093/neuonc/noac174.177

Vancouver

Lier S, Rein KA, Lund S, Lång A, Lång E, Meyer N et al. CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival. Neuro-Oncology. 2022;24(S2):ii51. https://doi.org/10.1093/neuonc/noac174.177

Author

Lier, S. ; Rein, Kjell Arne ; Lund, S. ; Lång, A. ; Lång, E. ; Meyer, N. ; Dutta, A. ; Anand, S. ; Nesse, G. ; Johansen, R. ; Klungland, A. ; Rinholm, J. ; Boe, S. ; Anand, A. ; Pollard, S. ; Lerdrup, M. ; Pandey, D. / CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival. In: Neuro-Oncology. 2022 ; Vol. 24, No. S2. pp. ii51.

Bibtex

@article{4362b2d0f38247aa94eb125fc5c3a975,
title = "CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival",
abstract = "BackgroundGlioblastoma 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 MethodsWe 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.ResultsCDK12/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.ConclusionThese results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for GBM.",
author = "S. Lier and Rein, {Kjell Arne} and S. Lund and A. L{\aa}ng and E. L{\aa}ng and N. Meyer and A. Dutta and S. Anand and G. Nesse and R. Johansen and A. Klungland and J. Rinholm and S. Boe and A. Anand and S. Pollard and M. Lerdrup and D. Pandey",
year = "2022",
doi = "10.1093/neuonc/noac174.177",
language = "English",
volume = "24",
pages = "ii51",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "S2",
note = "17th Meeting of the European-Association-of-Neuro-Oncology ; Conference date: 15-09-2022 Through 18-09-2022",

}

RIS

TY - ABST

T1 - CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival

AU - Lier, S.

AU - Rein, Kjell Arne

AU - Lund, S.

AU - Lång, A.

AU - Lång, E.

AU - Meyer, N.

AU - Dutta, A.

AU - Anand, S.

AU - Nesse, G.

AU - Johansen, R.

AU - Klungland, A.

AU - Rinholm, J.

AU - Boe, S.

AU - Anand, A.

AU - Pollard, S.

AU - Lerdrup, M.

AU - Pandey, D.

PY - 2022

Y1 - 2022

N2 - BackgroundGlioblastoma 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 MethodsWe 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.ResultsCDK12/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.ConclusionThese results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for GBM.

AB - BackgroundGlioblastoma 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 MethodsWe 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.ResultsCDK12/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.ConclusionThese results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for GBM.

U2 - 10.1093/neuonc/noac174.177

DO - 10.1093/neuonc/noac174.177

M3 - Conference abstract in journal

VL - 24

SP - ii51

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - S2

T2 - 17th Meeting of the European-Association-of-Neuro-Oncology

Y2 - 15 September 2022 through 18 September 2022

ER -

ID: 345409991