Antitumour efficacy of MEK inhibitors in human lung cancer cells and their derivatives with acquired resistance to different tyrosine kinase inhibitors.
Antitumour efficacy of MEK inhibitors in human lung cancer cells and their derivatives with acquired resistance to different tyrosine kinase inhibitors.
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DOI：
10.1038/bjc.2011.244
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发表时间：
2011-07-26
影响因子：
8.8
通讯作者：
Ciardiello, F.
中科院分区：
文献类型：
--
作者：
Morgillo, F.;Cascone, T.;D'Aiuto, E.;Martinelli, E.;Troiani, T.;Saintigny, P.;De Palma, R.;Heymach, J. V.;Berrino, L.;Tuccillo, C.;Ciardiello, F.
目的：研究癌细胞对四种不同酪氨酸激酶抑制剂(TKI)：厄洛替尼、吉非替尼、万德丹尼和索拉非尼耐药的分子机制。通过不断增加每种药物的剂量处理人肺腺癌细胞系CALU-3，建立了对这些TKI获得性耐药的体外模型。用安捷伦全基因组芯片进行转录图谱分析。采用Western印迹分析、酶联免疫吸附(ELISA)、四甲基偶氮唑蓝(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium)体外集落生长、迁移、侵袭和非锚定非依赖性集落生长实验，并对亲代(P)和TKI抗性(R)CALU-3细胞进行裸鼠移植瘤的体内实验。与P-CALU-3细胞相比，TKI-R CALU-3细胞中活化的、磷酸化的MET、IGF-1R、AKT、MEK、MAPK和Survivin的表达显著增加。4株TKI-RCALU-3细胞中E-钙粘蛋白和双调节蛋白α表达下调，波形蛋白、VE-钙粘蛋白、缺氧诱导因子-1和血管内皮生长因子受体-1mRNAs表达上调。四种TKI-R CALU-3细胞均表现出侵袭、迁移和锚定非依赖性生长的增加。综上所述，这些数据提示TKI-R CALU-3细胞上皮向间充质转化(EMT)。几种靶向AKT、MET或IGF-1R的药物处理不影响TKI-R CALU-3细胞的增殖。相反，MSC19363669B和Selumetinib这两种选择性MEK抑制剂处理后，对所有四种TKI-R CALU-3细胞系的细胞增殖、侵袭、迁移、体外非贴壁生长和体内肿瘤生长均有抑制作用。这些数据表明，EMT是四种不同TKI耐药的特征，在人CALU-3肺腺癌中，EMT对MEK抑制剂敏感。
To study the molecular mechanisms regulating cancer cell resistance to four different tyrosine kinase inhibitors (TKIs): erlotinib, gefitinib, vandetanib and sorafenib. An in vitro model of acquired resistance to these TKIs was developed by continuously treating the human lung adenocarcinoma cell line CALU-3 with escalating doses of each drug. Transcriptional profiling was performed with Agilent whole genome microarrays. Western blot analysis, enzyme-linked immunosorbent (ELISA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation, migration, invasion and anchorage-independent colony growth assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in parental (P) and TKI-resistant (R) CALU-3 cell lines. As compared with P-CALU-3 cells, in TKI-R CALU-3 cell lines a significant increase in the expression of activated, phosphorylated MET, IGF-1R, AKT, MEK, MAPK and of survivin was observed. Downregulation of E-cadherin and amphiregulin mRNAs and upregulation of vimentin, VE-cadherin, HIF-1α and vascular endothelial growth factor receptor-1 mRNAs were observed in all four TKI-R CALU-3 cell lines. All four TKI-R CALU-3 cells showed increased invasion, migration and anchorage-independent growth. Together, these data suggest epithelial to mesenchymal transition (EMT) in TKI-R CALU-3 cells. Treatment with several agents that target AKT, MET or IGF-1R did not affect TKI-R CALU-3 cell proliferation. In contrast, treatment with MSC19363669B and selumetinib, two selective MEK inhibitors, caused inhibition of cell proliferation, invasion, migration, anchorage-independent growth in vitro and of tumour growth in vivo of all four TKI-R CALU-3 cell lines. These data suggest that resistance to four different TKIs is characterised by EMT, which is MEK-inhibitor sensitive in human CALU-3 lung adenocarcinoma.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
11.5
作者：
Lind, Joline S. W.;Dingemans, Anne-Marie C.;Smit, Egbert F.
通讯作者：
Smit, Egbert F.
影响因子：
6.4
作者：
Janmaat, ML;Rodriguez, JA;Giaccone, G
通讯作者：
Giaccone, G
影响因子：
8
作者：
Matei, D;Emerson, RE;Donner, DB
通讯作者：
Donner, DB
影响因子：
56.9
作者：
Engelman, Jeffrey A.;Zejnullahu, Kreshnik;Janne, Pasi A.
通讯作者：
Janne, Pasi A.