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Disruption of Redox Balance Enhances the Effects of BRAF-inhibition in Melanoma Cells

View ORCID ProfileB. Bishal Paudel, Joshua E. Lewis, Keisha N. Hardeman, Corey E. Hayford, Charles J. Robbins, Simona G. Codreanu, Stacy D. Sherrod, John A. McLean, Melissa L. Kemp, View ORCID ProfileVito Quaranta
doi: https://doi.org/10.1101/818989
B. Bishal Paudel
1Department of Biochemistry, Vanderbilt University, Nashville, TN.
2Quantitative Systems Biology Center (QSBC), Vanderbilt University, Nashville, TN.
3Department of Biomedical Engineering, University of Virginia, Charlottesville, VA.
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  • ORCID record for B. Bishal Paudel
Joshua E. Lewis
4The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
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Keisha N. Hardeman
1Department of Biochemistry, Vanderbilt University, Nashville, TN.
2Quantitative Systems Biology Center (QSBC), Vanderbilt University, Nashville, TN.
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Corey E. Hayford
2Quantitative Systems Biology Center (QSBC), Vanderbilt University, Nashville, TN.
5Chemical and Physical Biology Graduate Program, Vanderbilt University, Nashville, TN.
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Charles J. Robbins
1Department of Biochemistry, Vanderbilt University, Nashville, TN.
2Quantitative Systems Biology Center (QSBC), Vanderbilt University, Nashville, TN.
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Simona G. Codreanu
6Center for Innovative Technology, Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN.
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Stacy D. Sherrod
6Center for Innovative Technology, Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN.
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John A. McLean
6Center for Innovative Technology, Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN.
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Melissa L. Kemp
4The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia
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Vito Quaranta
1Department of Biochemistry, Vanderbilt University, Nashville, TN.
2Quantitative Systems Biology Center (QSBC), Vanderbilt University, Nashville, TN.
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  • ORCID record for Vito Quaranta
  • For correspondence: vito.quaranta@vanderbilt.edu
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Abstract

Summary Melanomas harboring BRAF mutations can be treated with BRAF inhibitors (BRAFi), but responses are varied and tumor recurrence is inevitable. Here, using an integrative approach of experimentation and mathematical flux balance analyses in BRAF-mutated melanoma cells, we report that elevated antioxidant capacity is linked to BRAFi sensitivity in melanoma cells. High levels of antioxidant metabolites in cells with reduced BRAFi sensitivity confirm this conclusion. By extending our analyses to other melanoma subtypes in TCGA, 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.

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Posted October 28, 2019.
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Disruption of Redox Balance Enhances the Effects of BRAF-inhibition in Melanoma Cells
B. Bishal Paudel, Joshua E. Lewis, Keisha N. Hardeman, Corey E. Hayford, Charles J. Robbins, Simona G. Codreanu, Stacy D. Sherrod, John A. McLean, Melissa L. Kemp, Vito Quaranta
bioRxiv 818989; doi: https://doi.org/10.1101/818989
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Disruption of Redox Balance Enhances the Effects of BRAF-inhibition in Melanoma Cells
B. Bishal Paudel, Joshua E. Lewis, Keisha N. Hardeman, Corey E. Hayford, Charles J. Robbins, Simona G. Codreanu, Stacy D. Sherrod, John A. McLean, Melissa L. Kemp, Vito Quaranta
bioRxiv 818989; doi: https://doi.org/10.1101/818989

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