Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
Quantitative Systems Biology Center (QSBC), Vanderbilt University, Nashville, Tennessee.
Cancer Res. 2020 Oct 15;80(20):4565-4577. doi: 10.1158/0008-5472.CAN-19-3588.
Melanomas harboring mutations can be treated with inhibitors (i), but responses are varied and tumor recurrence is inevitable. Here we used an integrative approach of experimentation and mathematical flux balance analyses in -mutated melanoma cells to discover that elevated antioxidant capacity is linked to i sensitivity in melanoma cells. High levels of antioxidant metabolites in cells with reduced 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 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.
携带突变的黑色素瘤可以用抑制剂 (i) 治疗，但反应各不相同，肿瘤复发是不可避免的。在这里，我们使用突变黑色素瘤细胞的实验和数学通量平衡分析的综合方法来发现，抗氧化能力的提高与黑色素瘤细胞对 i 的敏感性有关。具有降低 i 敏感性的细胞中高水平的抗氧化代谢物证实了这一结论。通过将我们的分析扩展到癌症基因组图谱中的其他黑色素瘤亚型，我们预测氧化还原能力的提高是黑色素瘤的一个普遍特征，以前没有观察到。我们提出，氧化还原脆弱性可以被利用来获得治疗益处，并确定意想不到的联合靶点，以增强 i 在任何黑色素瘤中的疗效，无论其突变状态如何。意义：综合生物信息学、通量平衡分析和实验方法确定了可靶向的氧化还原脆弱性，并显示了调节癌症抗氧化防御的潜力，以增强现有疗法在黑色素瘤中的益处。
