| RRC ID |
67405
|
| 著者 |
Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A, Kubota K, Gemma A.
|
| タイトル |
Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer.
|
| ジャーナル |
Mol Cancer Ther
|
| Abstract |
Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR-138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors.
|
| 巻・号 |
14(11)
|
| ページ |
2433-40
|
| 公開日 |
2015-11-1
|
| DOI |
10.1158/1535-7163.MCT-15-0050
|
| PII |
1535-7163.MCT-15-0050
|
| PMID |
26351321
|
| MeSH |
ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B / metabolism
Blotting, Western
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Crizotinib
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Epithelial-Mesenchymal Transition / drug effects
Epithelial-Mesenchymal Transition / genetics
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic / drug effects
Humans
In Situ Hybridization, Fluorescence
Indoles / pharmacology
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Oligonucleotide Array Sequence Analysis
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-met / antagonists & inhibitors
Proto-Oncogene Proteins c-met / genetics*
Proto-Oncogene Proteins c-met / metabolism
Pyrazoles / pharmacology
Pyridines / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Sulfones / pharmacology
|
| IF |
5.615
|
| リソース情報 |
| ヒト・動物細胞 |
A549(RCB0098)
LC-2/ad(RCB0440) |
