Univ. Lille, INSERM, UMR-S1172, Jean Pierre Aubert Research Centre, 59045, Lille, France.
Laboratoire SPCMIB UMR CNRS 5068, Université Paul Sabatier, 118 Route de Narbonne, 31062, Toulouse Cedex 9, France.
Cell Death Dis. 2018 Feb 27;9(3):325. doi: 10.1038/s41419-018-0340-4.
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc-amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.
针对 BRAF 和 MEK 抑制剂组合的靶向治疗已被批准作为 BRAF 突变型黑色素瘤的一线治疗方法。然而，大多数患者在治疗几个月内就会出现疾病进展。在获得 BRAF 抑制剂（BRAFi）耐药的情况下，已经描述了代谢适应。BRAFi 耐药的黑色素瘤的特征是线粒体氧化磷酸化增加，并且更容易受到靶向线粒体药物诱导的细胞死亡。BRAFi 耐药的黑色素瘤还表现出由于线粒体耗氧量增加而导致的氧化应激增强。为了了解在氧化应激背景下 BRAFi 耐药黑色素瘤细胞存活的机制，我们建立了一种临床前小鼠模型，该模型准确地重现了对 MAPK 抑制剂（包括单独和联合使用几种 BRAF 或 MEK 抑制剂）获得耐药性的体内情况。使用小鼠模型和从小鼠肿瘤中生成的黑色素瘤细胞系，我们证实了耐药性的获得与线粒体氧化磷酸化的增加以及谷氨酰胺代谢的重要性有关。此外，我们已经证明，BRAFi 耐药的黑色素瘤可以适应线粒体代谢以支持葡萄糖衍生的谷氨酸合成，从而导致谷胱甘肽含量增加。此外，BRAFi 耐药的黑色素瘤表现出强烈的 NRF-2 通路激活，导致戊糖磷酸途径增加，该途径参与还原型谷胱甘肽的再生，并增加 xCT 表达，xCT 是 xc-氨基酸转运体的组成部分，对于细胞内谷胱甘肽合成所需的胱氨酸摄取至关重要。所有这些代谢修饰维持谷胱甘肽水平，并有助于细胞内氧化还原平衡，以允许 BRAFi 耐药黑色素瘤细胞存活。
