Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
Pigment Cell Melanoma Res. 2010 Apr;23(2):190-200. doi: 10.1111/j.1755-148X.2010.00685.x. Epub 2010 Feb 10.
BRAF(V600E/K) is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAF(V600E/K) and BRAF(WT) showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAF(V600E/K), it activated the pathway in the resistant BRAF(WT) cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAF(WT) melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control. Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions. The results suggest that the drug can confer an advantage to BRAF(WT) primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.
BRAF(V600E/K) 是黑色素瘤中一种常见的突变激活肿瘤特异性激酶，目前针对该激酶的特异性抑制剂 PLX4032 已被用于治疗。我们对 BRAF(V600E/K) 和 BRAF(WT) 黑色素瘤肿瘤细胞的研究表明，矛盾的是，PLX4032 虽然抑制了高度敏感的 BRAF(V600E/K) 中的 ERK1/2，但通过 RAF1 的激活，它在耐药的 BRAF(WT) 细胞中激活了该通路，而不管 NRAS 或 PTEN 突变的状态如何。持续激活的 ERK1/2 在 BRAF(WT) 黑色素瘤细胞中触发下游效应物，并诱导与细胞周期控制相关的广谱基因表达的变化。此外，PLX4032 增加了生长因子依赖性 NRAS Q61L 突变型原发性黑色素瘤细胞的增殖速度，降低了细胞黏附性，并增加了晚期病变细胞的迁移能力。这些结果表明，该药物可以为体内的 BRAF(WT) 原发性和转移性肿瘤细胞提供优势，并为监测临床反应提供标志物。
