Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells
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Shuhei Suzuki1,2, Masashi Okada1, Hiroyuki Takeda1,2, Kenta Kuramoto1, Tomomi Sanomachi1,2, Keita Togashi1,3, Shizuka Seino1,4, Masahiro Yamamoto1, Takashi Yoshioka2 and Chifumi Kitanaka1,4
1Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan
2Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
3Department of Ophthalmology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
4Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
Chifumi Kitanaka, email: firstname.lastname@example.org
Masashi Okada, email: email@example.com
Keywords: non-small-cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); tyrosine kinase inhibitor (TKI); glycolysis; animal model
Received: April 05, 2018 Accepted: July 29, 2018 Published: August 24, 2018
Use of epidermal growth factor receptor (EGFR) inhibitors represented by gefitinib and erlotinib has become the standard of treatment for non-small-cell lung cancers (NSCLCs) with activating EGFR mutations. However, the majority of NSCLCs, which overexpress EGFR without such mutations, are resistant to EGFR inhibitors, and the mechanism(s) behind such primary resistance of NSCLCs without activating EGFR mutations to EGFR inhibitors still remains poorly understood. Here in this study, we show that glucose metabolism mediated by GLUT1, a facilitative glucose transporter, is involved in gefitinib resistance of NSCLC cells. We found that GLUT1 expression and glucose uptake were increased in resistant NSCLC cells after gefitinib treatment and that genetic as well as pharmacological inhibition of GLUT1 sensitized not only NSCLC cells with primary resistance but also those with acquired resistance to gefitinib. In vivo, the combination of systemic gefitinib and a GLUT1 inhibitor, both of which failed to inhibit tumor growth when administered alone, significantly inhibited the growth of xenograft tumors formed by the implantation of NSCLC cells with wild-type EGFR (wt-EGFR). Since our data indicated that GLUT1 was similarly involved in erlotinib resistance, our findings suggest that the activity of GLUT1-mediated glucose metabolism could be a critical determinant for the sensitivity of NSCLC cells to EGFR inhibitors and that concurrent GLUT1 inhibition may therefore be a mechanism-based approach to treating NSCLCs resistant to EGFR inhibitors, including those with wt-EGFR.
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