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CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma

Author

Listed:
  • Thibault Houles

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Geneviève Lavoie

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Sami Nourreddine

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    University of California, San Diego)

  • Winnie Cheung

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Éric Vaillancourt-Jean

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Célia M. Guérin

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Mathieu Bouttier

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Benoit Grondin

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    Université du Québec à Montréal)

  • Sichun Lin

    (University of Toronto)

  • Marc K. Saba-El-Leil

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique)

  • Stephane Angers

    (University of Toronto
    University of Toronto
    University of Toronto)

  • Sylvain Meloche

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    Université de Montréal)

  • Philippe P. Roux

    (Université de Montréal, Montreal, 2950, Chemin de la Polytechnique
    Faculty of Medicine, Université de Montréal)

Abstract

Melanoma is the deadliest form of skin cancer and considered intrinsically resistant to chemotherapy. Nearly all melanomas harbor mutations that activate the RAS/mitogen-activated protein kinase (MAPK) pathway, which contributes to drug resistance via poorly described mechanisms. Herein we show that the RAS/MAPK pathway regulates the activity of cyclin-dependent kinase 12 (CDK12), which is a transcriptional CDK required for genomic stability. We find that melanoma cells harbor constitutively high CDK12 activity, and that its inhibition decreases the expression of long genes containing multiple exons, including many genes involved in DNA repair. Conversely, our results show that CDK12 inhibition promotes the expression of short genes with few exons, including many growth-promoting genes regulated by the AP-1 and NF-κB transcription factors. Inhibition of these pathways strongly synergize with CDK12 inhibitors to suppress melanoma growth, suggesting promising drug combinations for more effective melanoma treatment.

Suggested Citation

  • Thibault Houles & Geneviève Lavoie & Sami Nourreddine & Winnie Cheung & Éric Vaillancourt-Jean & Célia M. Guérin & Mathieu Bouttier & Benoit Grondin & Sichun Lin & Marc K. Saba-El-Leil & Stephane Ange, 2022. "CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34179-8
    DOI: 10.1038/s41467-022-34179-8
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    References listed on IDEAS

    as
    1. Nicholas Kwiatkowski & Tinghu Zhang & Peter B. Rahl & Brian J. Abraham & Jessica Reddy & Scott B. Ficarro & Anahita Dastur & Arnaud Amzallag & Sridhar Ramaswamy & Bethany Tesar & Catherine E. Jenkins , 2014. "Targeting transcription regulation in cancer with a covalent CDK7 inhibitor," Nature, Nature, vol. 511(7511), pages 616-620, July.
    2. Sara J. Dubbury & Paul L. Boutz & Phillip A. Sharp, 2018. "CDK12 regulates DNA repair genes by suppressing intronic polyadenylation," Nature, Nature, vol. 564(7734), pages 141-145, December.
    3. Chong Sun & Liqin Wang & Sidong Huang & Guus J. J. E. Heynen & Anirudh Prahallad & Caroline Robert & John Haanen & Christian Blank & Jelle Wesseling & Stefan M. Willems & Davide Zecchin & Sebastijan H, 2014. "Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma," Nature, Nature, vol. 508(7494), pages 118-122, April.
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