PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.
PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.
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DOI：
10.1111/j.1755-148x.2010.00685.x
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发表时间：
2010-04
影响因子：
4.3
通讯作者：
Sznol M
中科院分区：
文献类型：
--
作者：
Halaban R;Zhang W;Bacchiocchi A;Cheng E;Parisi F;Ariyan S;Krauthammer M;McCusker JP;Kluger Y;Sznol M
BRAFV600E/K是黑色素瘤中常见的突变活性肿瘤特异性激酶，目前被特异性抑制剂PLX4032靶向治疗。我们对BRAFV600E/K和BRAFWT黑色素瘤细胞的研究表明，矛盾的是，虽然PLX4032抑制了高度敏感的BRAFV600E/K中的ERK1/2，但它通过激活RAF1激活了耐药BRAFWT细胞中的通路，而不管NRAS或PTEN的突变状态如何。持续活跃的ERK1/2触发BRAFWT黑色素瘤细胞中的下游效应物，并诱导与细胞周期控制相关的广泛基因表达的变化。此外，PLX4032增加了生长因子依赖性NRAS Q61L突变原发性黑色素瘤细胞的增殖率，降低了细胞粘附性，增加了晚期病变细胞的移动性。结果表明，该药物可以在体内赋予BRAFWT原发和转移性肿瘤细胞优势，并为监测临床反应提供标志物。
BRAFV600E/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 BRAFV600E/K and BRAFWT showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAFV600E/K, it activated the pathway in the resistant BRAFWT cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAFWT 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 BRAFWT primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.