論文 - 詳細
| RRC ID | 38151 |
|---|---|
| 著者 | Yamada T, Matsumoto K, Wang W, Li Q, Nishioka Y, Sekido Y, Sone S, Yano S. |
| タイトル | Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the most frequent cause of acquired resistance to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib, in lung cancer. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR. EXPERIMENTAL DESIGN:CL-387,785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors. RESULTS:HGF reduced susceptibility to CL-387,785 in H1975 cells. Western blotting and small interfering RNA analyses indicated that HGF-induced hyposensitivity was mediated by the MET/phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR, ErbB2, ErbB3, and ErbB4. Hyposensitivity of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts. The hyposensitivity was abrogated by treatment with anti-HGF neutralizing antibody, HGF antagonist NK4, or MET-TKI. CONCLUSIONS:We showed HGF-mediated hyposensitivity as a novel mechanism of resistance to irreversible EGFR-TKIs. It will be clinically valuable to investigate the involvement of HGF-MET-mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR. |
| 巻・号 | 16(1) |
| ページ | 174-83 |
| 公開日 | 2010-1-1 |
| DOI | 10.1158/1078-0432.CCR-09-1204 |
| PII | 1078-0432.CCR-09-1204 |
| PMID | 20008840 |
| MeSH | Adenocarcinoma / drug therapy* Adenocarcinoma / genetics Drug Resistance, Neoplasm ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics* Fibroblasts / metabolism Hepatocyte Growth Factor / pharmacology* Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Mitogen-Activated Protein Kinase 3 / metabolism Mutation Protein Kinase Inhibitors / therapeutic use* Protein-Tyrosine Kinases / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-met / metabolism Receptors, Growth Factor / metabolism Signal Transduction |
| IF | 10.107 |
| 引用数 | 78 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5 |