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)