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

• Published in: Nature communications 2022-10, Vol.13 (1), p.6457-6457, Article 6457
• Main Authors: Houles, Thibault, Lavoie, Geneviève, Nourreddine, Sami, Cheung, Winnie, Vaillancourt-Jean, Éric, Guérin, Célia M., Bouttier, Mathieu, Grondin, Benoit, Lin, Sichun, Saba-El-Leil, Marc K., Angers, Stephane, Meloche, Sylvain, Roux, Philippe P.
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 13/89; 13/95; 38/70; 45/29; 45/91; 631/45/475/2290; 631/67/1059/2326; 631/67/1813/1634; 64/60; 82/58; Activator protein 1; Cell Line, Tumor; Chemoresistance; Chemotherapy; Cyclin-dependent kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Deoxyribonucleic acid; DNA; DNA repair; Drug resistance; Exons; Gene expression; Genes; Humanities and Social Sciences; Humans; Kinases; MAP kinase; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; Mutation; NF-κB protein; Protein kinase; Proteins; Proto-Oncogene Proteins B-raf - metabolism; Ras protein; Science; Science (multidisciplinary); Skin cancer; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Synergism; Therapeutic targets; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34179-8

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. In patients with melanoma, increased RAS/mitogen-activated protein kinase (MAPK) pathway activity is known to drive chemotherapy resistance. Here, the authors identify CDK12 as a downstream effector of the RAS/MAPK pathway and therapeutic target which mediates chemotherapy resistance through increased expression of DNA repair associated genes.