Our study shows that the MOGP approach was able to rank the impact of genomic features on melanoma cell lines’ responses to three BRAF inhibitors, identifying BRAF and NRAS mutations as consistently critical predictors while also highlighting the previously underappreciated role of EZH2 mutations that might offer insights into differing drug sensitivities and potential resistance pathways in melanoma therapies. This evidence concerns the gene EZH2 and melanoma.