CDK12 inhibition reveals melanoma dependence on the RUNX1/CBFβ complex for genomic stability

  • Cell Rep. 2025 Nov 25;44(11):116495. doi: 10.1016/j.celrep.2025.116495.
Jonathan Boucher  1 ,  Thibault Houles  2 ,  Elsa Berliocchi  2 ,  Geneviève Lavoie  2 ,  Graham MacLeod  3 ,  Marc K Saba-El-Leil  2 ,  Stephane Angers  4 ,  Sylvain Meloche  5 ,  Philippe P Roux  6
Affiliations
  • 1. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada. Electronic address: [email protected].
  • 2. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada.
  • 3. Donnelly Centre for Cellular & Biomolecular Research, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • 4. Donnelly Centre for Cellular & Biomolecular Research, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • 5. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada; Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
  • 6. Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada. Electronic address: [email protected].
PMID: 41176765 DOI: 10.1016/j.celrep.2025.116495
Abstract

Cutaneous melanoma is the deadliest form of skin Cancer, frequently driven by hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Cyclin-dependent kinase 12 (CDK12), a downstream effector of MAPK signaling, has emerged as a therapeutic target due to its essential role in transcriptional regulation and DNA damage repair. To identify vulnerabilities associated with CDK12 inhibition, we performed a genome-wide CRISPR-Cas9 screen and identified the Runt-related transcription factor RUNX1 and its cofactor CBFβ as synthetic lethal partners of CDK12. RUNX1 inhibition enhanced melanoma sensitivity to CDK12 inhibitors in a p53-independent manner, resulting in DNA damage accumulation and impaired repair capacity. Combined inhibition of CDK12 and RUNX1 suppressed melanoma growth in vivo. These findings identify RUNX1/CBFβ as a compensatory mechanism in CDK12-inhibited melanoma and define a synthetic lethal interaction with translational potential for combinatorial therapy.

Keywords
CBFB; CDK12; CP: cancer; CRISP-Cas9 screening; DNA damage response; RUNX1; genomic stability; melanoma; p53-independent pathway; therapeutic vulnerability; transcriptional regulation.
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