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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.

Original publication

DOI

10.1016/j.ccr.2013.05.009

Type

Journal article

Journal

Cancer Cell

Publication Date

08/07/2013

Volume

24

Pages

105 - 119

Keywords

Apoptosis, Catechin, Cell Differentiation, Cell Line, Tumor, DNA Damage, E2F1 Transcription Factor, Humans, Melanoma, Methotrexate, Microphthalmia-Associated Transcription Factor, Phenotype, Thymine Nucleotides