Résumé
The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. This type of cancer is highly resistant to conventional DNA-damaging chemotherapeutics, and intense research has been dedicated for understanding the molecular pathways underlying chemoresistance. The Ras/mitogen-activated protein kinase (MAPK) signalling pathway is often deregulated in melanoma, which frequently harbours activating mutations in NRAS or BRAF. Herein, we demonstrate that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) contributes to melanoma chemoresistance by altering their response to chemotherapeutic agents. We find that RSK phosphorylates checkpoint kinase 1 (Chk1) at an inhibitory site, Ser280, both in vitro and in vivo. Our results indicate that RSK is the predominant protein kinase operating downstream of mitogens and oncogenes of the Ras/MAPK pathway, and consistent with this, we find that RSK constitutively phosphorylates Chk1 in melanoma. We show that RSK inhibition increases Chk1 activity in response to DNA-damaging agents, suggesting that the Ras/MAPK pathway modulates Chk1 function and the response to DNA damage. Accordingly, we demonstrate that RSK promotes G2 DNA damage checkpoint silencing in a Chk1-dependent manner, and find that RSK inhibitors sensitize melanoma cells to DNA-damaging agents. Together, our results identify a novel link between the Ras/MAPK pathway and the DNA damage response, and suggest that RSK inhibitors may be used to modulate chemosensitivity, which is one of the major obstacles to melanoma treatment.