Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis

• Published in: British journal of cancer Vol. 95; no. 11; pp. 1504 - 1513
• Main Authors: YOKOYAMA, H, IKEHARA, Y, NAKANISHI, H, KODERA, Y, IKEHARA, S, YATABE, Y, MOCHIZUKI, Y, KOIKE, M, FUJIWARA, M, NAKAO, A, TATEMATSU, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 04-12-2006
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Blotting, Western; Breast cancer; Cancer research; Cancer therapies; Cell Line, Tumor; Drug Resistance, Neoplasm - physiology; Enzyme-Linked Immunosorbent Assay; Epidermal growth factor; Flow Cytometry; Gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Gefitinib; Humans; Immunohistochemistry; Kinases; Ligands; Liver; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lung cancer; Male; Medical research; Medical sciences; Metastasis; Mice; Mice, Nude; Mutation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Proteins; Quinazolines - pharmacology; Receptor, ErbB-2 - metabolism; Stomach Neoplasms - metabolism; Stomach Neoplasms - secondary; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Translational Therapeutics; Tumors; United States > US; Japan; Antineoplastic agent; Acquired; Quinazoline derivatives; erbB2 Gene; Hepatic disease; Monoclonal antibody; Stomach cancer; gastric cancer; liver metastasis; gefitinib; trastuzumab; HER2; P13K/Akt; Epidermal growth factor receptor; Liver cancer; Cancerology; Anticytokine; Established cell line; Gefitinib; Protein-tyrosine kinase; Tumor cell; Protooncogene; Gastric disease; Human; Treatment resistance; Enzyme; Transferases; Enzyme inhibitor; Akt protein kinase; Malignant tumor; Human Epidermal growth factor Receptor 2; Sensitivity resistance; C-Onc gene; Digestive diseases; drug resistance; Molecular biology; Trastuzumab; Liver metastasis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603459

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.