Addition of S-1 to the Epidermal Growth Factor Receptor Inhibitor Gefitinib Overcomes Gefitinib Resistance in Non-small cell Lung Cancer Cell Lines with MET Amplification
Addition of S-1 to the Epidermal Growth Factor Receptor Inhibitor Gefitinib Overcomes Gefitinib Resistance in Non-small cell Lung Cancer Cell Lines with MET Amplification
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DOI：
10.1158/1078-0432.ccr-08-2251
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发表时间：
2009-02-01
影响因子：
11.5
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Okabe, Takafumi;Okamoto, Isamu;Nakagawa, Kazuhiko
目的：大多数具有表皮生长因子受体（EGFR）激活突变的非小细胞肺癌（NSCLC）肿瘤最初对吉非替尼和厄洛替尼等EGFR酪氨酸激酶抑制剂（EGFR-TKI）有反应，但它们几乎总是对这些药物产生耐药性。EGFR（T790 M）的继发性突变和MET原癌基因扩增已被确定为EGFR-TKI获得性耐药的机制。我们现在已经研究了是否除了口服氟嘧啶衍生物S-1吉非替尼可能克服gefitinib耐药在NSCLC细胞line.Experimental设计：gefitinib对EGFR信号传导和表达的影响，胸苷酸合成酶和转录因子E2 F-1在吉非替尼耐药NSCLC细胞进行了检查免疫印迹分析。S-1（或5-氟尿嘧啶）和吉非替尼对非小细胞肺癌细胞的生长的影响进行了检查，在体外，以及在nukemies.Results：吉非替尼诱导下调胸苷酸合成酶和E2 F-1在吉非替尼耐药的非小细胞肺癌细胞MET扩增，但不是在那些窝藏EGFR的T790 M突变。5-氟尿嘧啶和吉非替尼的组合协同抑制具有MET扩增的细胞增殖，但是。而不是那些EGFR T790 M突变的人。同样，S-1和吉非替尼的组合协同抑制生长，只有NSCLC异种移植与MET amplification.Conclusions：我们的研究结果表明，除了S-1的EGFR-TKI是一个很有前途的策略，克服EGFR-TKI耐药的NSCLC与MET扩增。
Purpose: Most non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET protooncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines.Experimental Design: The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice.Results: Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-flucrouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, bur. not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification.Conclusions: Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.