Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells.
Involvement of GLUT1-mediated glucose transport and metabolism in gefitinib resistance of non-small-cell lung cancer cells.
复制标题
DOI：
10.18632/oncotarget.25994
复制
发表时间：
2018-08-24
期刊：
影响因子：
--
通讯作者：
Kitanaka C
中科院分区：
文献类型：
--
作者：
Suzuki S;Okada M;Takeda H;Kuramoto K;Sanomachi T;Togashi K;Seino S;Yamamoto M;Yoshioka T;Kitanaka C
以吉非替尼和厄洛替尼为代表的表皮生长因子受体（EGFR）抑制剂的使用已成为EGFR激活突变型非小细胞肺癌（NSCLC）的治疗标准。然而，大多数非小细胞肺癌（其过表达EGFR而无此类突变）对EGFR抑制剂具有耐药性，并且对EGFR抑制剂无激活EGFR突变的非小细胞肺癌的此类原发性耐药性背后的机制仍然知之甚少。在本研究中，我们发现由葡萄糖转运蛋白GLUT 1介导的葡萄糖代谢参与了NSCLC细胞对吉非替尼的耐药。我们发现，GLUT 1表达和葡萄糖摄取增加耐药的NSCLC细胞后，吉非替尼治疗和GLUT 1的遗传以及药理学抑制敏化不仅与原发性耐药的NSCLC细胞，但也与获得性耐药吉非替尼。在体内，全身性吉非替尼和GLUT 1抑制剂（两者单独给药时均不能抑制肿瘤生长）的组合显著抑制了通过植入具有野生型EGFR（wt-EGFR）的NSCLC细胞形成的异种移植肿瘤的生长。由于我们的数据表明GLUT 1与厄洛替尼耐药类似，我们的研究结果表明GLUT 1介导的葡萄糖代谢活性可能是NSCLC细胞对EGFR抑制剂敏感性的关键决定因素，因此同时抑制GLUT 1可能是治疗EGFR抑制剂耐药NSCLC的一种基于机制的方法，包括那些携带wt-EGFR的NSCLC。
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.