Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma.
Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma.
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DOI：
10.18632/oncotarget.24871
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发表时间：
2018-04-10
期刊：
影响因子：
--
通讯作者：
Deaglio, Silvia
中科院分区：
文献类型：
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作者：
Audrito, Valentina;Manago, Antonella;Deaglio, Silvia
携带BRAF突变的转移性黑素瘤代表仍未满足的医疗需求，因为BRAF抑制剂的成功受到耐药性发展的限制。烟酰胺磷酸核糖转移酶（NAMPT）是NAD生物合成的关键酶。细胞外形式（eNAMPT）具有类精氨酸功能，并在炎症性疾病（包括癌症）中上调。在这里，我们表明，eNAMPT是积极释放的黑色素瘤细胞系的培养上清液。此外，对BRAF抑制剂（BiR）产生抗性的细胞显示出eNAMPT水平的显著增加。与无肿瘤动物相比，来自异种移植有BiR细胞系的小鼠的血浆含有更高的eNAMPT水平。一致地，与50例局部疾病或38例健康供体相比，113例BRAF突变转移性黑色素瘤患者的eNAMPT水平升高，显示与肿瘤负荷标志物（如LDH）或侵袭性疾病（如PD-L1）直接相关。从50例患者的系列分析中推断，对BRAF/MEK抑制剂治疗的反应中，eNAMPT浓度降低，但在进展时再次升高。最后，高的eNAMPT水平与显著较短的总生存期相关。我们的研究结果表明，eNAMPT是携带BRAF突变的转移性黑色素瘤患者的肿瘤负荷和治疗反应的新标志物。
Metastatic melanoma carrying BRAF mutations represent a still unmet medical need as success of BRAF inhibitors is limited by development of resistance. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD biosynthesis. An extracellular form (eNAMPT) possesses cytokine-like functions and is up-regulated in inflammatory disorders, including cancer. Here we show that eNAMPT is actively released in culture supernatants of melanoma cell lines. Furthermore, cells that become resistant to BRAF inhibitors (BiR) show a significant increase of eNAMPT levels. Plasma from mice xenografted with BiR cell lines contain higher eNAMPT levels compared to tumor-free animals. Consistently, eNAMPT levels are elevated in 113 patients with BRAF-mutated metastatic melanoma compared to 50 with localized disease or to 38 healthy donors, showing a direct correlation with markers of tumor burden, such as LDH, or aggressive disease (such as PD-L1). eNAMPT concentrations decrease in response to therapy with BRAF/MEK inhibitors, but increase again at progression, as inferred from the serial analysis of 50 patients. Lastly, high eNAMPT levels correlate with a significantly shorter overall survival. Our findings suggest that eNAMPT is a novel marker of tumor burden and response to therapy in patients with metastatic melanoma carrying BRAF mutations.