title: Cetuximab-induced insulin-like growth factor receptor I activation mediates cetuximab resistance in gastric cancer cells.
abstract: Epidermal growth factor receptor (EGFR) and insulin‑like growth factor receptor‑I (IGF‑IR) are frequently overexpressed in gastric cancer cells. However, these cells are resistant to the anti‑EGFR monoclonal antibody cetuximab. The aim of the present study was to determine whether cetuximab resistance in gastric cancer cells resulted from activation of the IGF‑IR signaling pathway by cetuximab. The results demonstrated that EGFR phosphorylation was markedly inhibited in gastric cancer cell lines (SGC7901 and MGC803) which possessed functional K‑ras and BRAF following treatment with cetuximab. However, cetuximab treatment did not diminish cell viability; by contrast, IGF‑IR activation was observed. Knockdown of IGF‑IR or the use of an IGF‑IR inhibitor were found to increase the sensitivity of gastric cancer cells to cetuximab. Furthermore, cetuximab induced phosphorylation of the non‑receptor tyrosine kinase c‑steroid receptor co‑activator (Src). Treatment of gastric cancer cells with a Src inhibitor was shown to significantly reduce cetuximab‑induced phosphorylation of IGF‑IR as well as Src, which resulted in enhanced sensitivity to cetuximab treatment. In conclusion, the results of the present study demonstrated that cetuximab‑induced IGF‑IR activation was involved in cetuximab resistance in gastric cancer cells and that Src was an important mediator for IGF‑IR activation.
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Heming
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China.
authors.forename: Zhitu
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000970:Antineoplastic Agents; D007093:Imidazoles; D011719:Pyrazines; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab