Increased inflammatory lipid metabolism and anaplerotic mitochondrial activation follow acquired resistance to vemurafenib in BRAF-mutant melanoma cells
Increased inflammatory lipid metabolism and anaplerotic mitochondrial activation follow acquired resistance to vemurafenib in BRAF-mutant melanoma cells
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DOI：
10.1038/s41416-019-0628-x
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发表时间：
2020-01-01
影响因子：
8.8
通讯作者：
Beloueche-Babari, Mounia
中科院分区：
文献类型：
--
作者：
Delgado-Goni, Teresa;Galobart, Teresa Casals;Beloueche-Babari, Mounia
BRAF抑制剂，如vemurafenib，在BRAF突变黑色素瘤治疗中显示出疗效，但总是会出现获得性耐药。揭示与vemurafenib耐药相关的潜在脆弱性可以为联合治疗提供合理的策略。方法研究三个braf突变的人黑色素瘤细胞克隆的代谢特征和获得性vemurafenib耐药性的脆弱性，分析基线和营养戒断条件下的代谢谱、基因和蛋白表达。临床前发现与来自公开临床数据集的基因表达分析相关。结果两个vemurafenib耐药克隆显示出对脂质代谢的依赖和前列腺素E2合成的增加，并且在EGFR抑制下对vemurafenib更敏感，这可能暗示炎症脂质和EGFR信号在ERK再激活和vemurafenib耐药中起作用。第三个耐药无性系显示出较高的丙酮酸羧化酶（PC）活性，表明线粒体递变代谢增加，同时GLUT-1降低，PC蛋白表达增加，在营养匮乏条件下具有生存优势。前列腺素合成酶（PTGES）的表达与黑色素瘤患者的生存率呈负相关。在一些BRAF抑制剂治疗进展的患者中，观察到PC和PTGES基因表达增加。总之，我们的数据突出了braf突变黑色素瘤获得性vemurafenib耐药过程中代谢适应的异质性，可能揭示了联合治疗靶向的关键临床相关机制。
Background BRAF inhibitors, such as vemurafenib, have shown efficacy in BRAF-mutant melanoma treatment but acquired-resistance invariably develops. Unveiling the potential vulnerabilities associated with vemurafenib resistance could provide rational strategies for combinatorial treatment. Methods This work investigates the metabolic characteristics and vulnerabilities of acquired resistance to vemurafenib in three generated BRAF-mutant human melanoma cell clones, analysing metabolic profiles, gene and protein expression in baseline and nutrient withdrawal conditions. Preclinical findings are correlated with gene expression analysis from publicly available clinical datasets. Results Two vemurafenib-resistant clones showed dependency on lipid metabolism and increased prostaglandin E2 synthesis and were more responsive to vemurafenib under EGFR inhibition, potentially implicating inflammatory lipid and EGFR signalling in ERK reactivation and vemurafenib resistance. The third resistant clone showed higher pyruvate-carboxylase (PC) activity indicating increased anaplerotic mitochondrial metabolism, concomitant with reduced GLUT-1, increased PC protein expression and survival advantage under nutrient-depleted conditions. Prostaglandin synthase (PTGES) expression was inversely correlated with melanoma patient survival. Increases in PC and PTGES gene expression were observed in some patients following progression on BRAF inhibitors. Conclusions Altogether, our data highlight heterogeneity in metabolic adaptations during acquired resistance to vemurafenib in BRAF-mutant melanoma, potentially uncovering key clinically-relevant mechanisms for combinatorial therapeutic targeting.