We observed that MAPK inhibitors treatment efficacy and patients’ PFS, in the presence of elevated LDH level and brain metastasis, depended on the mutation type of the TERT promoter, highlighting, first, the functional link that exists between TERT biology and the MAPK pathway, and second, a specific behavior of the TERT c.-124C>T mutations in a specific subset of poor prognosis melanomas. The gene discussed is TERT; the disease is melanoma.