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
|
リソース情報 |
ヒト・動物細胞 |
MKN45(RCB1001) |