Like other tumors, advanced melanomas include a mix of cells with different genetics and behaviors. For example, some melanoma cells don’t divide rapidly. These differences can help some melanoma cells evade targeted therapies, making it impossible to kill off the tumor. Now, researchers report a new combination treatment that sidesteps resistance: methotrexate, a conventional chemotherapy drug, and TMECG, a new toxic molecule made by the researchers. Methotrexate pushes melanoma cells to divide and to make a protein called tyrosinase. The new toxic molecule TMECG is activated by tyrosinase, and so then targets the melanoma cells. Besides being specific to melanomas, this new combination treatment works on tumors that have resisted all other therapies.
“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.”