論文 - 詳細
| RRC ID | 65828 |
|---|---|
| 著者 | Nanjo S, Arai S, Wang W, Takeuchi S, Yamada T, Hata A, Katakami N, Okada Y, Yano S. |
| タイトル | MET Copy Number Gain Is Associated with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR-mutant Lung Cancer. |
| ジャーナル | Mol Cancer Ther |
| Abstract |
Leptomeningeal carcinomatosis occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek for a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P < 0.01). To study molecular mechanisms of acquired EGFR-TKI resistance in leptomeningeal carcinomatosis, we utilized our previously developed mouse model of leptomeningeal carcinomatosis with the EGFR-mutant lung cancer cell line PC-9/ffluc cells, in which acquired resistance to gefitinib was induced by continuous oral treatment. Compared with subcutaneously inoculated gefitinib-resistant tumors, the T790M mutation was less frequent in leptomeningeal carcinomatosis that acquired resistance to gefitinib. PC-9/LMC-GR cells were established from the gefitinib-resistant leptomeningeal carcinomatosis model, and they were found to be intermediately resistant to gefitinib and osimertinib (third-generation EGFR-TKI). Although EGFR-T790M was negative, gefitinib resistance of PC-9/LMC-GR cells was related to MET copy number gain with MET activation. Moreover, combined use of EGFR-TKI and crizotinib, a MET inhibitor, dramatically regressed leptomeningeal carcinomatosis with acquired resistance to gefitinib or osimertinib. These findings suggest that combination therapy with MET inhibitors may be promising for controlling leptomeningeal carcinomatosis that acquires resistance to EGFR-TKIs. Mol Cancer Ther; 16(3); 506-15. ©2017 AACR. |
| 巻・号 | 16(3) |
| ページ | 506-515 |
| 公開日 | 2017-3-1 |
| DOI | 10.1158/1535-7163.MCT-16-0522 |
| PII | 1535-7163.MCT-16-0522 |
| PMID | 28138027 |
| MeSH | Animals Antineoplastic Agents / pharmacology* Cell Line, Tumor Disease Models, Animal Drug Resistance, Neoplasm / genetics* ErbB Receptors / genetics Female Gefitinib Gene Dosage* Humans Lung Neoplasms / genetics Meningeal Carcinomatosis / diagnosis Meningeal Carcinomatosis / drug therapy Meningeal Carcinomatosis / genetics* Mice Mutation Neoplasms, Second Primary* Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-met / genetics* Quinazolines / pharmacology* Xenograft Model Antitumor Assays |
| IF | 5.615 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5(RCB0218) |