American Association for Cancer Research
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Supplemental Table 1. Supplemental Table 2. Supplemental Table 3. from Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

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journal contribution
posted on 2023-04-03, 14:27 authored by Teppei Sugano, Masahiro Seike, Rintaro Noro, Chie Soeno, Mika Chiba, Fenfei Zou, Shinji Nakamichi, Nobuhiko Nishijima, Masaru Matsumoto, Akihiko Miyanaga, Kaoru Kubota, Akihiko Gemma

Supplemental Table 1. Gene copy numbers of MET, EGFR and KRAS in EBC-1R cells Supplemental Table 2. MiRNAs correlated with the sensitivity to PHA665752 Supplemental Table 3. ABCB1 protein expression in 50 lung squamous cell cancer patients 



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. Mol Cancer Ther; 14(11); 2433–40. ©2015 AACR.

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