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

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 uncover 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 uncover RUNX1/CBFβ as a compensatory mechanism in CDK12-inhibited melanoma and establish a novel synthetic lethal interaction with translational potential for combinatorial therapy. RNA-seq profiling of A375 melanoma cells treated with SR-4835 (CDK12 inhibitor, 100 nM), AI-10-49 (RUNX1 inhibitor, 1 µM), or the combination for 48 hours, compared to DMSO-treated controls.