MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines.
MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines.
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DOI：
10.1038/bjc.2011.298
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发表时间：
2011-09-06
影响因子：
8.8
通讯作者：
Albanell, J.
中科院分区：
文献类型：
--
作者：
Arriola, E.;Canadas, I.;Arumi-Uria, M.;Domine, M.;Lopez-Vilarino, J. A.;Arpi, O.;Salido, M.;Menendez, S.;Grande, E.;Hirsch, F. R.;Serrano, S.;Bellosillo, B.;Rojo, F.;Rovira, A.;Albanell, J.
小细胞肺癌（SCLC）预后较差，并且仍然是靶向治疗的孤儿。 MET 在多种肿瘤类型中被激活，可能是一个有前途的治疗靶点。为了评估 MET 在 SCLC 中的作用，在一组 SCLC 细胞系中评估了 MET 基因状态和蛋白质表达。 MET 抑制剂 PHA-665752 用于研究基础和肝细胞生长因子 (HGF) 刺激条件下通路抑制的效果。在人类 SCLC 样本中进行 MET 和 p-MET 的免疫组织化学分析，并评估与结果的关联。在 MET 突变型 SCLC 细胞中，HGF 诱导 MET 磷酸化，增加增殖、侵袭性和克隆生长。 PHA-665752 阻断 MET 磷酸化并抵消 HGF 诱导的作用。在临床样本中，总 MET 和 p-MET 过度表达分别在 54% 和 43% SCLC 肿瘤中检测到 (n=77)。与 p-MET 阴性病例（287 天）相比，MET 磷酸化与中位总生存期较差（132 天）相关（P<0.001）。 Phospho-MET 在多变量分析中保留了其预后价值。 MET 激活导致 MET 突变型 SCLC 细胞更具侵袭性，而 PHA-665752 的抑制作用则逆转了这种表型。在 SCLC 患者中，MET 激活与较差的预后相关，这表明 MET 激活与该疾病的不良临床行为有关。
Small cell lung carcinoma (SCLC) has poor prognosis and remains orphan from targeted therapy. MET is activated in several tumour types and may be a promising therapeutic target. To evaluate the role of MET in SCLC, MET gene status and protein expression were evaluated in a panel of SCLC cell lines. The MET inhibitor PHA-665752 was used to study effects of pathway inhibition in basal and hepatocyte growth factor (HGF)-stimulated conditions. Immunohistochemistry for MET and p-MET was performed in human SCLC samples and association with outcome was assessed. In MET mutant SCLC cells, HGF induced MET phosphorylation, increased proliferation, invasiveness and clonogenic growth. PHA-665752 blocked MET phosphorylation and counteracted HGF-induced effects. In clinical samples, total MET and p-MET overexpression were detected in 54% and 43% SCLC tumours (n=77), respectively. MET phosphorylation was associated with poor median overall survival (132 days) vs p-MET negative cases (287 days)(P<0.001). Phospho-MET retained its prognostic value in a multivariate analysis. MET activation resulted in a more aggressive phenotype in MET mutant SCLC cells and its inhibition by PHA-665752 reversed this phenotype. In patients with SCLC, MET activation was associated with worse prognosis, suggesting a role in the adverse clinical behaviour in this disease.
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DOI：
10.1615/jenvironpatholtoxicoloncol.v28.i2.10
发表时间：
2009
期刊：
Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer
影响因子：
--
作者：
Kanteti R;Yala S;Ferguson MK;Salgia R
通讯作者：
Salgia R
DOI：
10.1073/pnas.95.24.14379
发表时间：
1998-11-24
影响因子：
11.1
作者：
Bardelli, A;Longati, P;Comoglio, PM
通讯作者：
Comoglio, PM
影响因子：
64.8
作者：
GIORDANO, S;PONZETTO, C;COMOGLIO, PM
通讯作者：
COMOGLIO, PM
影响因子：
15.9
作者：
Comoglio, PM;Trusolino, L
通讯作者：
Trusolino, L
DOI：
10.1002/hed.21383
发表时间：
2010-12-01
影响因子：
2.9
作者：
Kim, Chul-Ho;Koh, Yoon Woo;Choi, Eun Chang
通讯作者：
Choi, Eun Chang