Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET Inhibitors in Non-Small Cell Lung Cancer.
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.
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Teppei
T
Sugano
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan. mseike@nms.ac.jp.
Masahiro
M
Seike
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Rintaro
R
Noro
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Chie
C
Soeno
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Mika
M
Chiba
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Fenfei
F
Zou
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Shinji
S
Nakamichi
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Nobuhiko
N
Nishijima
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Masaru
M
Matsumoto
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Akihiko
A
Miyanaga
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Kaoru
K
Kubota
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi, Bunkyo-ku, Tokyo, Japan.
Akihiko
A
Gemma
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000494:pharmacology
C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met