Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma
Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma
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DOI：
10.1016/j.canlet.2018.11.018
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发表时间：
2019-02-01
期刊：
影响因子：
9.7
通讯作者：
Renner, Kathrin
中科院分区：
文献类型：
--
作者：
Brummer, Christina;Faerber, Stephanie;Renner, Kathrin
包括黑色素瘤在内的肿瘤通常表现为葡萄糖代谢加速。在大约50%的黑色素瘤中检测到v-Raf小鼠肉瘤病毒癌基因同源B(BRAF)的突变，导致糖酵解进一步增强。因此，抗代谢物质可能会增强RAF抑制剂的作用。我们已经确定了两种非类固醇抗炎药(NSAIDs)双氯芬酸和鲁米拉昔布能够通过靶向乳酸释放和氧化磷酸化(OXPHOS)来限制人类黑色素瘤细胞的能量代谢。与RAF抑制剂维莫拉非尼联合使用时，观察到了很强的协同作用：双氯芬酸和鲁米拉昔布增强了维莫拉非尼的抗糖酵解作用，并阻止了RAF抑制剂诱导的OXPHOS代谢重编程。因此，两种非甾体抗炎药都能使黑色素瘤细胞对维莫拉非尼增敏，并使RAF抑制剂的抗肿瘤作用从细胞抑制作用增强到细胞毒作用。此外，NSAIDs的加入延缓了RAF抑制剂耐药的发生，这很可能是通过对抗MITF的上调而实现的。我们的数据表明，选定的非甾体抗炎药可能成为MAPK途径抑制剂治疗BRAF(V600E)突变黑色素瘤的有前途的组合伙伴。
Tumors, including melanomas, frequently show an accelerated glucose metabolism. Mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF), detected in about 50% of all melanomas, result in further enhancement of glycolysis. Therefore anti-metabolic substances might enhance the impact of RAF inhibitors. We have identified the two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib being able to restrict energy metabolism in human melanoma cells by targeting lactate release and oxidative phosphorylation (OXPHOS). In combination with the RAF inhibitor vemurafenib strong synergism was observed: Diclofenac as well as lumiracoxib increased the anti-glycolytic impact of vemurafenib and prevented RAF-inhibitor induced metabolic reprogramming towards OXPHOS. Consequently, both NSAIDs sensitized melanoma cells to vemurafenib triggered proliferation arrest and enhanced the anti-tumor effect of RAF inhibitors from cytostatic to cytotoxic. Furthermore the addition of NSAIDs delayed the onset of RAF inhibitor resistance, most likely by counteracting the upregulation of MITF. Our data suggest that selected NSAIDs could be a promising combination partner for MAPK pathway inhibitors for the treatment of BRAF(V600E) mutated melanomas.