An Integrative Gene Expression and Mathematical Flux Balance Analysis Identifies Targetable Redox Vulnerabilities in Melanoma Cells

Abstract

Melanomas harboring <i>BRAF</i> mutations can be treated with <i>BRAF</i> inhibitors (<i>BRAF</i>i), but responses are varied and tumor recurrence is inevitable. Here we used an integrative approach of experimentation and mathematical flux balance analyses in <i>BRAF</i>-mutated melanoma cells to discover that elevated antioxidant capacity is linked to <i>BRAF</i>i sensitivity in melanoma cells. High levels of antioxidant metabolites in cells with reduced <i>BRAF</i>i sensitivity confirmed this conclusion. By extending our analyses to other melanoma subtypes in The Cancer Genome Atlas, we predict that elevated redox capacity is a general feature of melanomas, not previously observed. We propose that redox vulnerabilities could be exploited for therapeutic benefits and identify unsuspected combination targets to enhance the effects of <i>BRAF</i>i in any melanoma, regardless of mutational status. SIGNIFICANCE: An integrative bioinformatics, flux balance analysis, and experimental approach identify targetable redox vulnerabilities and show the potential for modulation of cancer antioxidant defense to augment the benefits of existing therapies in melanoma.