Directed Phenotype Switching as an Effective Antimelanoma Strategy
Menée in vitro et in vivo, cette étude suggère l'intérêt d'un traitement combinant le méthotrexate et un promédicament appelé TMECG pour les patients atteints d'un mélanome métastatique, indépendamment de la présence de mutations BRAF, MEK ou p53
Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation-associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-( )-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status. "Methotrexate eradicates invasive melanoma cells via upregulation of MITF "Methotrexate-mediated phenotype switching promotes tyrosinase expression "A tyrosinase-activated prodrug TMECG kills melanoma cells by dTTP depletion "Methotrexate/TMECG induces apoptosis in melanoma irrespective of BRAF or p53 status