Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis.
Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis.
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在源自肝转移的HER2过表达的HER2过表达的人类胃癌细胞系中，敏感性并获得了对吉非尼的抗性的分子基础。
DOI：
10.1038/sj.bjc.6603459
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发表时间：
2006-12-04
影响因子：
8.8
通讯作者：
Nakanishi, H
中科院分区：
文献类型：
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作者：
Yokoyama, H;Ikehara, Y;Kodera, Y;Ikehara, S;Yatabe, Y;Mochizuki, Y;Koike, M;Fujiwara, M;Nakao, A;Tatematsu, M;Nakanishi, H
发现转移至肝脏的胃癌过度表达HER 2的发生率显著高于原发性胃癌。本研究的目的是探讨针对HER 2过表达的胃癌肝转移分子治疗的可能性。我们开发了三个新的HER 2过表达胃癌细胞系（GLM-1，GLM-2，GLM-4）没有表皮生长因子受体（EGFR）突变来自这样的肝转移，其中两个有HER 2基因扩增。所有这些GLM系列细胞系在体外对吉非替尼（EGFR酪氨酸激酶的特异性抑制剂（易瑞沙）而不是抗HER 2抗体曲妥珠单抗（赫赛汀））高度敏感，而大多数HER 2低表达对应物则不敏感。在这些HER 2过表达的GLM系列中，蛋白激酶B（Akt），而不是细胞外信号调节激酶1/2（ERK 1/2），被组成性磷酸化，吉非替尼有效抑制Akt磷酸化，在体外诱导强烈的细胞凋亡，并在裸鼠肿瘤异种移植物中表现出抗肿瘤活性。这种吉非替尼介导的异种移植物抗肿瘤作用通过曲妥珠单抗治疗显著增强。另一方面，吉非替尼耐药细胞（GLM-1 R）表现出EGFR表达增加，随后是丝裂原活化蛋白激酶（MAPK）通路的组成性激活。这些结果表明，吉非替尼的抗肿瘤作用是由于有效抑制HER 2驱动的磷脂酰肌醇-3-激酶（PI 3 K）/Akt通路的组成性激活，而对吉非替尼的获得性耐药是由于Ras/MAPK通路的组成性激活以补偿PI 3 K/Akt通路。HER 2过表达的胃癌肝转移可能是吉非替尼和曲妥珠单抗潜在的分子靶点。
Gastric cancer metastasised to the liver was found to overexpress HER2 at a significantly higher incidence than primary gastric cancers. The purpose of the present study was to investigate the possibility of molecular therapy targeting HER2 overexpression in gastric cancer liver metastasis. We developed three new HER2-overexpressing gastric cancer cell lines (GLM-1, GLM-2, GLM-4) without epidermal growth factor receptor (EGFR) mutations derived from such liver metastasis, two of which had HER2 gene amplifications. All these GLM series of cell lines were highly sensitive to gefitinib in vitro, a specific inhibitor of EGFR tyrosine kinase (Iressa) rather than anti-HER2 antibody trastuzumab (Herceptin), whereas most of the HER2 low-expressing counterparts were not. In these HER2-overexpressing GLM series, protein kinase B (Akt), but not extracellular signal-regulated kinase 1/2 (ERK1/2), was constitutively phosphorylated, and gefitinib efficiently inhibited this Akt phosphorylation, induced strong apoptosis in vitro and exhibited antitumour activity in tumour xenografts in nude mice. This gefitinib-mediated antitumour effect in xenograft was significantly potentiated by trastuzumab treatment. On the other hand, gefitinib-resistant cells (GLM-1R) exhibited increased EGFR expression, followed by constitutive activation of mitogen-activated protein kinase (MAPK) pathway. These results suggest that the antitumour effect of gefitinib is due to the effective inhibition of HER2-driven constitutive activation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway, and that the acquired resistance to gefitinib is due to the constitutive activation of Ras/MAPK pathway in compensation for PI3K/Akt pathway. Gastric cancer liver metastasis with HER2 overexpression would be a potential molecular target for gefitinib and trastuzumab.