論文 - 詳細
| RRC ID | 61988 |
|---|---|
| 著者 | Funakoshi Y, Mukohara T, Ekyalongo RC, Tomioka H, Kataoka Y, Shimono Y, Chayahara N, Toyoda M, Kiyota N, Fujiwara Y, Minami H. |
| タイトル | Regulation of MET kinase inhibitor resistance by copy number of MET in gastric carcinoma cells. |
| ジャーナル | Oncol Res |
| Abstract |
We previously established acquired resistant models for MET-tyrosine kinase inhibitors (TKIs) by continuously exposing the MET-amplified gastric cancer cell line MKN45 to MET-TKIs, PHA665752 (MKN45-PR), or GSK1363089 (MKN45-GR). We found resistant mechanisms caused by increased copy number of MET in both lines and Y1230H mutation in MKN45-PR. We also found that excessive MET signaling caused by these MET alterations resulted in intra-S-phase arrest in the absence of MET-TKIs, so that cells grew faster in the presence of MET-TKIs, a phenomenon referred to as "addiction." In this study, to investigate reversibility of the acquired resistance and "addiction" to MET-TKIs and their causative MET alterations, we sequentially cultured MKN45-PR and MKN45-GR in decreasing concentrations of MET-TKIs until they were able to grow in a drug-free condition. These "revertant" cell lines (designated MKN45-PR-RE and MKN45-GR-RE) were comparatively analyzed. Growth assay showed that both MKN45-PR-RE and MKN45-GR-RE partially lost the property of "addiction" to MET-TKIs. MKN45-GR-RE lost the property of resistance to GSK1363089, but MKN45-PR-RE retained resistance to PHA665752. Copy numbers and expression and phosphorylation of MET protein reduced in both MKN45-PR-RE and MKN45-GR-RE compared with MKN45-PR and MKN45-GR, respectively, but Y1230H mutation and biochemical resistance to PHA665752 remained in MKN45-PR-RE. The "addiction" to MET-TKIs appeared attributable to increased copy number, and the property and the MET alteration were reversible. The Y1230H mutation appeared enough in itself to keep cells resistant to MET-TKIs and was irreversible. |
| 巻・号 | 21(6) |
| ページ | 287-93 |
| 公開日 | 2013-1-1 |
| DOI | 10.3727/096504014X13946388748956 |
| PMID | 25198658 |
| MeSH | Carcinoma / genetics* Carcinoma / metabolism Cell Line, Tumor Cell Proliferation / drug effects DNA Mutational Analysis Dose-Response Relationship, Drug Drug Resistance, Neoplasm / genetics* Gene Dosage* Humans Mutation Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-met / antagonists & inhibitors* Proto-Oncogene Proteins c-met / genetics* Signal Transduction / drug effects Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism |
| IF | 4.949 |
| 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 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 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 | MKN45(RCB1001) |