曲美替尼
甲状腺间变性癌
MEK抑制剂
达布拉芬尼
癌症研究
威罗菲尼
MAPK/ERK通路
下调和上调
细胞周期
生物
细胞生长
癌症
激酶
甲状腺癌
黑色素瘤
细胞生物学
转移性黑色素瘤
基因
生物化学
遗传学
作者
K. Kurata,Naoyoshi Onoda,Shinichi Noda,Shinichiro Kashiwagi,Yuka Asano,Kosei Hirakawa,Masaichi Ohira
标识
DOI:10.3892/ijo.2016.3723
摘要
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated. Dabrafenib strongly inhibited the viability in BRAF mutated cells by demonstrating G0/G1-arrest via the downregulation of MEK/ERK phosphorylation. Upregulated phosphorylation of MEK was observed in RAS mutated cells after dabrafenib treatment and caused VEGF upregulation, but was not related to the cellular proliferation. Trametinib inhibited the cellular viability to variable degrees in every cell by downregulating ERK phosphorylation. Dual blockade by both inhibitors demonstrated clear cytostatic effect in all the cells. OCUT-4 showed the weakest sensitivity to trametinib, no additional effect of either inhibitor in combination with the other, and an increase of SNAI1 mRNA expression after treatment with inhibitors, suggesting a mechanism for resistance. Our findings demonstrated the efficacy of a mutation-selective BRAF inhibitor and a MEK inhibitor in human ATC cells in a genetic alteration-specific manner.
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