Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo.
Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo.
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DOI：
10.1038/bjc.2014.519
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发表时间：
2014-10-28
影响因子：
8.8
通讯作者：
Santin, A. D.
中科院分区：
文献类型：
--
作者：
Schwab, C. L.;Bellone, S.;English, D. P.;Roque, D. M.;Lopez, S.;Cocco, E.;Nicoletti, R.;Bortolomai, I.;Bonazzoli, E.;Ratner, E.;Silasi, D-A;Azodi, M.;Schwartz, P. E.;Rutherford, T. J.;Santin, A. D.
关键词：
子宫浆液性癌 (USC) 是一种侵袭性子宫癌，可能依赖 HER2/neu 扩增作为增殖驱动因素。本文的目的是评估有或没有 HER2/neu 基因扩增的 USC 细胞系对不可逆 ErbB 酪氨酸激酶抑制剂阿法替尼的敏感性，并测试阿法替尼治疗 HER2 扩增的 USC 异种移植物的疗效。十五个原代 USC 细胞系中的八个（四个具有 HER2 扩增，四个没有）表现出相似的体外生长率，并用标量浓度的阿法替尼进行处理。通过流式细胞术测定对细胞生长、信号传导和细胞周期分布的影响。通过强饲法对携带 HER2/neu 扩增 USC 异种移植物的小鼠进行阿法替尼治疗，以确定对肿瘤生长和总体生存的影响。携带 HER2/neu 基因扩增的原代化疗耐药 USC 细胞系对阿法替尼暴露极其敏感（平均值±sem. IC50=0.0056±0.0006μM），并且明显比 HER2/neu 非扩增 USC 细胞系更敏感（平均值±sem. IC50=0.563±0.092μM， P<0.0001）。阿法替尼暴露导致 HER2/neu 过表达 USC 中细胞存活的终止、HER2/neu 自身磷酸化和 S6 转录因子磷酸化的抑制，并抑制 HER2 扩增的肿瘤异种移植物的生长，从而提高总体存活率 (P=0.0017)。阿法替尼可能对 HER2/neu 扩增化疗耐药的 USC 非常有效。有必要对携带 HER2/neu 扩增 USC 的患者进行阿法替尼研究。
Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean±s.e.m. IC50=0.0056±0.0006 μM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean±s.e.m. IC50=0.563±0.092 μM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.
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影响因子：
28.2
作者：
Takezawa K;Pirazzoli V;Arcila ME;Nebhan CA;Song X;de Stanchina E;Ohashi K;Janjigian YY;Spitzler PJ;Melnick MA;Riely GJ;Kris MG;Miller VA;Ladanyi M;Politi K;Pao W
通讯作者：
Pao W
影响因子：
8
作者：
Hartman, Z.;Zhao, H.;Agazie, Y. M.
通讯作者：
Agazie, Y. M.
DOI：
10.1155/2012/743193
发表时间：
2012
期刊：
Chemotherapy research and practice
影响因子：
--
作者：
Mitri Z;Constantine T;O'Regan R
通讯作者：
O'Regan R
影响因子：
--
作者：
Reungwetwattana T;Dy GK
通讯作者：
Dy GK
影响因子：
8.8
作者：
通讯作者：
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