Ball Douglas W, Jin Ning, Rosen D Marc, Dackiw Alan, Sidransky David, Xing Mingzhao, Nelkin Barry D
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 553, Baltimore, Maryland 21231-1000, USA.
J Clin Endocrinol Metab. 2007 Dec;92(12):4712-8. doi: 10.1210/jc.2007-1184. Epub 2007 Sep 18.
Activating mutations in the BRAF gene, primarily at V600E, are associated with poorer outcomes in patients with papillary thyroid cancer. MAPK kinase (MEK), immediately downstream of BRAF, is a promising target for ras-raf-MEK-ERK pathway inhibition.
The objective of the investigation was to study the efficacy of a MEK1/2 inhibitor in thyroid cancer preclinical models with defined BRAF mutation status.
After treatment with the potent MEK 1/2 inhibitor AZD6244, MEK inhibition and cell growth were examined in four BRAF mutant (V600E) and two BRAF wild-type thyroid cancer cell lines and in xenografts from a BRAF mutant cell line.
AZD6244 potently inhibited MEK 1/2 activity in thyroid cancer cell lines regardless of BRAF mutation status, as evidenced by reduced ERK phosphorylation. Four BRAF mutant lines exhibited growth inhibition at low doses of the drug, with GI50 concentrations ranging from 14 to 50 nm, predominantly via a G0/G1 arrest, comparable with findings in a sensitive BRAF mutant melanoma cell line. In contrast, two BRAF wild-type lines were significantly less sensitive, with GI50 values greater than 200 nm. Nude mouse xenograft tumors derived from the BRAF mutant line ARO exhibited dose-dependent growth inhibition by AZD6244, with effective treatment at 10 mg/kg by oral gavage. This effect was primarily cytostatic and associated with marked inhibition of ERK phosphorylation.
AZD6244 inhibits the MEK-ERK pathway across a spectrum of thyroid cancer cells. MEK inhibition is cytostatic in papillary thyroid cancer and anaplastic thyroid cancer cells bearing a BRAF mutation and may have less impact on thyroid cancer cells lacking this mutation.
BRAF基因的激活突变，主要是V600E突变，与甲状腺乳头状癌患者的预后较差有关。BRAF下游紧邻的丝裂原活化蛋白激酶（MEK）是抑制ras-raf-MEK-ERK通路的一个有前景的靶点。
本研究旨在探讨MEK1/2抑制剂在具有明确BRAF突变状态的甲状腺癌临床前模型中的疗效。
用强效MEK 1/2抑制剂AZD6244处理后，在4种BRAF突变（V600E）和2种BRAF野生型甲状腺癌细胞系以及一种BRAF突变细胞系的异种移植瘤中检测MEK抑制作用和细胞生长情况。
无论BRAF突变状态如何，AZD6244均能有效抑制甲状腺癌细胞系中的MEK 1/2活性，这可通过ERK磷酸化水平降低得到证实。4种BRAF突变细胞系在低剂量药物作用下表现出生长抑制，半数生长抑制浓度（GI50）范围为14至50 nM，主要通过G0/G1期阻滞实现，这与在敏感的BRAF突变黑色素瘤细胞系中的发现相似。相比之下，2种BRAF野生型细胞系的敏感性明显较低，GI50值大于200 nM。源自BRAF突变细胞系ARO的裸鼠异种移植瘤表现出AZD6244剂量依赖性生长抑制，口服灌胃10 mg/kg可有效治疗。这种作用主要是细胞生长抑制性的，并且与ERK磷酸化的显著抑制相关。
AZD6244可抑制多种甲状腺癌细胞中的MEK-ERK通路。MEK抑制在携带BRAF突变的甲状腺乳头状癌和间变性甲状腺癌细胞中具有细胞生长抑制作用，而对缺乏该突变的甲状腺癌细胞影响较小。
