Work

Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells

Year: 2018

Type: article

Abstract: // Shuhei Suzuki 1, 2 , Masashi Okada 1 , Hiroyuki Takeda 1, 2 , Kenta Kuramoto 1 , Tomomi Sanomachi 1, 2 , Keita Togashi 1, 3 , Shizuka Seino 1, 4 , Masahiro Yamamoto 1 , Takashi Yoshioka 2 and Chifumi Kitanaka 1, 4 1 Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan 2 Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan 3 Department of Ophthalmology, Yamagata University School of Medicine, Yamagata 990-9585, Japan 4 Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan Correspondence to: Chifumi Kitanaka, email: [email protected] Masashi Okada, email: [email protected] 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 ABSTRACT 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.25994