論文 - 詳細
| RRC ID | 77170 |
|---|---|
| 著者 | Funakoshi Y, Mukohara T, Tomioka H, Ekyalongo RC, Kataoka Y, Inui Y, Kawamori Y, Toyoda M, Kiyota N, Fujiwara Y, Minami H. |
| タイトル | Excessive MET signaling causes acquired resistance and addiction to MET inhibitors in the MKN45 gastric cancer cell line. |
| ジャーナル | Invest New Drugs |
| Abstract |
The clinical efficacy of MET tyrosine kinase inhibitors (MET-TKIs) is hindered by the emergence of acquired resistance, presenting an obstacle to drug discovery. To clarify the mechanisms underlying acquired resistance to MET-TKIs, we established resistance models by continuous exposure of the MET-amplified gastric cancer cell line MKN45 to MET-TKIs, PHA665752 (MKN45-PR) and GSK1363089 (MKN45-GR). Baseline expression and phosphorylation of MET were elevated in MKN45-PR and MKN45-GR compared to MKN45 cells, and higher concentrations of MET-TKIs were required to inhibit MET phosphorylation compared to parental cells. Alterations in MET previously associated with resistance to MET-TKIs were observed in resistant cells, including elevated MET copy number, observed in both resistant lines compared to MKN45 cells, and the Y1230H mutation, detected in MKN45-PR cells. Notably, the growth of resistant lines was lower in the absence of MET-TKIs, suggesting "addiction" to inhibitors. While MKN45-PR cells exhibited a higher S-phase fraction in the absence of PHA665752, bromodeoxyuridine (BrdU) uptake was identical. Baseline phosphorylation of ATR, Chk1 and p53 and p21(waf1/Cip1) expression was higher in MKN45-PR compared to MKN45 cells, and levels were reduced to those observed in untreated MKN45 cells following PHA665752 treatment. Furthermore, targeted knockdown of MET enhanced the growth of MKN45-PR cells. These findings suggest that alterations in MET leading to acquired MET-TKI resistance, may cause excessive MET signaling, subsequent replication stress and DNA damage response, and intra-S-phase arrest in the absence of MET-TKIs. Thus, partial MET inhibition is necessary for resistant cells to proliferate, a phenomenon we refer to as MET-TKI "addiction". |
| 巻・号 | 31(5) |
| ページ | 1158-68 |
| 公開日 | 2013-10-1 |
| DOI | 10.1007/s10637-013-9959-2 |
| PMID | 23568717 |
| MeSH | Antineoplastic Agents / pharmacology* Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects DNA Damage Drug Resistance, Neoplasm / physiology* Humans Indoles / pharmacology* Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-met / antagonists & inhibitors Proto-Oncogene Proteins c-met / genetics Proto-Oncogene Proteins c-met / metabolism* RNA, Small Interfering / genetics Signal Transduction Stomach Neoplasms Sulfones / pharmacology* |
| IF | 3.525 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Patent(IFI CLAIMS) |
| 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) |