Identification of CDK12 as a new target of the RAS/MAPK pathway: implications for the treatment of melanoma
Published on November 24, 2022
Melanoma is a particularly aggressive form of skin cancer. Being intrinsically resistant to chemotherapy, melanoma is the cause of many deaths. The laboratory of Professor Philippe P. Roux, Director of the Cell Signalling and Proteomics Research Unit at IRIC, focused on the mechanisms associated with this resistance. To discover more effective anti-cancer targets, the team sought to identify the key effectors of the RAS/MAPK pathway, a signaling pathway that is overactivated in melanoma. The work carried out identified the CDK12 protein as a direct target of this pathway and highlighted its important role in melanoma cells. The project was led by postdoctoral fellow Thibault Houles and is the subject of a publication in the journal Nature Communications.
A hyperactivated target in melanoma cells
Using a proteomics approach, CDK12 was identified as a potential target of the RAS/MAPK pathway. Biochemical experiments subsequently verified that CDK12 is directly phosphorylated following activation of the pathway, and that this phosphorylation positively regulates its activity. Since the RAS/MAPK pathway is hyperactivated in melanoma cells, the team was interested in the activity levels of CDK12. They observed that the activity of CDK12 is also elevated, suggesting that CDK12 is indeed regulated by the RAS/MAPK pathway in these cells.
Possible therapeutic combinations
The researchers then wanted to understand the role of CDK12 in melanoma. Through transcriptomic analysis, the team found that CDK12 regulates the expression of genes according to their length. Its inhibition increases the expression of short genes comprising few exons in the cell lines tested. Interestingly, they observed the upregulation of the AP-1 and NF-κB pathways, both involved in cell growth, survival and proliferation. cancerous. Inhibition of these pathways sensitize melanoma cells to CDK12 inhibition: the combination of inhibitors synergistically reduces the proliferation and survival of the treated cells.
In sum, this work has identified CDK12 as a potential therapeutic target and proposes effective co-treatments that could eventually be exploited in the clinic.
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 Angers, Sylvain Meloche, Philippe P Roux. CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma. Nature Communications. 2022;13:6457