Copper Chelation Inhibits BRAF(V600E)-Driven Melanomagenesis and Counters Resistance to BRAF(V600E) and MEK1/2 Inhibitors.
Copper Chelation Inhibits BRAF(V600E)-Driven Melanomagenesis and Counters Resistance to BRAF(V600E) and MEK1/2 Inhibitors.
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DOI：
10.1158/0008-5472.can-16-1190
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发表时间：
2017-11-15
期刊：
影响因子：
11.2
通讯作者：
Counter CM
中科院分区：
文献类型：
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作者：
Brady DC;Crowe MS;Greenberg DN;Counter CM
MEK 1/2和BRAFV 600 E抑制剂用于治疗BRAFV 600 E阳性黑色素瘤，其他癌症正在评估中。铜输入的遗传干扰或用临床铜螯合剂TTM药理学减少铜抑制MEK 1/2激酶活性并减少BRAFV 600 E驱动的肿瘤发生。在这项研究中，我们报告说，TTM抑制转化生长的黑色素瘤细胞系耐BRAF或MEK 1/2抑制剂，并增强这些抑制剂的抗肿瘤活性。TTM还在黑色素瘤的基因工程小鼠模型中提供了生存优势，并且当考虑假定的过量给药时，倾向于增加BRAF抑制提供的生存获益。这种效应通过遗传抑制肿瘤中的铜输入而表现出来，这与MAPK信号传导的减少有关。因此，TTM降低铜水平和MAPK信号传导，从而抑制BRAFV 600 E驱动的黑色素瘤肿瘤生长。这些观察结果为TTM在黑色素瘤中的临床评价提供了信息和支持。
MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacological reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAFV600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended towards an increase in the survival benefit afforded by BRAF inhibition. This effect was phenocopied by genetically inhibiting copper import in tumors, which was linked to a reduction in MAPK signaling. Thus, TTM reduces copper levels and MAPK signaling, thereby inhibiting BRAFV600E-driven melanoma tumor growth. These observations inform and support clinical evaluation of TTM in melanoma.