論文 - 詳細
| RRC ID | 43596 |
|---|---|
| 著者 | Yamada T, Takeuchi S, Kita K, Bando H, Nakamura T, Matsumoto K, Yano S. |
| タイトル | Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer. |
| ジャーナル | J Thorac Oncol |
| Abstract |
INTRODUCTION:Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. METHODS:Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. RESULTS:HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by coculture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. CONCLUSIONS:HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status. |
| 巻・号 | 7(2) |
| ページ | 272-80 |
| 公開日 | 2012-2-1 |
| DOI | 10.1097/JTO.0b013e3182398e69 |
| PII | S1556-0864(15)33228-7 |
| PMID | 22089117 |
| MeSH | Adenocarcinoma / drug therapy* Adenocarcinoma / genetics Adenocarcinoma / metabolism Animals Antibodies, Anti-Idiotypic / pharmacology* Antibodies, Monoclonal / pharmacology Antibodies, Monoclonal, Humanized Blotting, Western Cell Line Cell Proliferation Cetuximab Drug Resistance, Neoplasm* ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics ErbB Receptors / immunology ErbB Receptors / metabolism* Female Fibroblasts / cytology Fibroblasts / metabolism Hepatocyte Growth Factor / pharmacology* Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / metabolism Mice Mice, SCID Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Mutation / genetics Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-met / metabolism RNA, Small Interfering / genetics Signal Transduction |
| IF | 13.357 |
| 引用数 | 34 |
| WOS 分野 | RESPIRATORY SYSTEM ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5 |