Résumé
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.
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•CDK12 expression associates with aggressiveness in cutaneous melanoma•CRISPR screen identifies RUNX1/CBFβ as synthetic lethal with CDK12 inhibition•Dual inhibition of CDK12 and RUNX1 synergistically disrupts melanoma growth•Synthetic lethality is p53 independent and driven by impaired DNA repair
Boucher et al. identify RUNX1/CBFβ as a synthetic lethal partner of CDK12 in melanoma. Co-inhibition of CDK12 and RUNX1 impairs DNA repair, increases DNA damage, and reduces tumor growth in vivo, highlighting a therapeutic vulnerability across melanoma genotypes.