Abstract：
:Melanomas harboring BRAF mutations can be treated with BRAF inhibitors (BRAFi), but responses are varied and tumor recurrence is inevitable. Here we used an integrative approach of experimentation and mathematical flux balance analyses in BRAF-mutated melanoma cells to discover that elevated antioxidant capacity is linked to BRAFi sensitivity in melanoma cells. High levels of antioxidant metabolites in cells with reduced BRAFi 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 BRAFi 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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Paudel BB,Lewis JE,Hardeman KN,Hayford CE,Robbins CJ,Stauffer PE,Codreanu SG,Sherrod SD,McLean JA,Kemp ML,Quaranta Vdoi
10.1158/0008-5472.CAN-19-3588subject
Has Abstractpub_date
2020-10-15 00:00:00pages
4565-4577issue
20eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-3588journal_volume
80pub_type
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