In the current study, we tested combination treatments with a MEK inhibitor, trametinib, and MDM2 inhibitors, nutlin-3/RG7388/HDM201, in BRAFV600E/p53WT melanoma cell lines, and explored the potential mechanism for the observed synergistic response to these combinations, revealing DUSP6 as a key connector for regulation between the MAPK and p53 pathways, and involvement of the ataxia telangiectasia (ATM) kinase. Here, MDM2 is linked to melanoma.