多个对PLX4032敏感的小鼠BRAF（V600E）黑色素瘤细胞系。
Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032.
作者信息
Jenkins Molly H, Steinberg Shannon M, Alexander Matthew P, Fisher Jan L, Ernstoff Marc S, Turk Mary Jo, Mullins David W, Brinckerhoff Constance E
机构信息
Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
出版信息
Pigment Cell Melanoma Res. 2014 May;27(3):495-501. doi: 10.1111/pcmr.12220. Epub 2014 Mar 6.
The BRAF mutation, which approaches 50% in human melanomas, constitutively activates pERK and contributes to disease progression. The BRAF inhibitor, Vemurafenib (PLX4032), shows promising clinical responses, but resistance to PLX4032 usually develops within a year. Transgenic mouse models allow the study of BRaf melanoma , however models are necessary to better understand the molecular mechanism underlying disease progression and resistance. We established melanoma cell lines (D4M cells) from the conditional mouse model of metastatic melanoma: , which recapitulates human disease. Cultured D4M cells express high constitutive pERK. PLX4032 abrogates ERK phosphorylation, inhibits D4M proliferation, and increases expression of the melanoma associated antigen, pmel, , consistent with human BRAF melanoma cell lines. D4M cells are transplantable in either immune-compromised or syngeneic B6 mice. Thus, D4M cell lines allow correlation of studies on molecular mechanisms of melanoma with investigations on pathology and immunology.
BRAF突变在人类黑色素瘤中的发生率接近50%，它可组成性激活pERK并促进疾病进展。BRAF抑制剂维莫非尼（PLX4032）显示出有前景的临床反应，但对PLX4032的耐药性通常在一年内就会出现。转基因小鼠模型有助于对BRAF黑色素瘤进行研究，然而，还需要其他模型来更好地理解疾病进展和耐药性背后的分子机制。我们从转移性黑色素瘤的条件性小鼠模型中建立了黑色素瘤细胞系（D4M细胞），该模型可重现人类疾病。培养的D4M细胞组成性表达高水平的pERK。PLX4032可消除ERK磷酸化，抑制D4M细胞增殖，并增加黑色素瘤相关抗原pmel的表达，这与人类BRAF黑色素瘤细胞系一致。D4M细胞可移植到免疫缺陷或同基因B6小鼠体内。因此，D4M细胞系能够将黑色素瘤分子机制的研究与病理学和免疫学研究联系起来。
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