Investigation of the mechanism of gefitinib resistance by comprehensive genetic analysis

综合基因分析研究吉非替尼耐药机制

• 批准号: 24790822
• 负责人: TERAI Hideki
• 金额: $ 2.66万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24790822/
• 关键词: EGFR-TKI; 肺癌; 薬剤耐性; イレッサ; ゲフィチニブ; 獲得耐性; FGF2; FGFR1; FGFR; EGFR-TKI耐性化; DNAメチル化; エピジェネティクス

Almost all patients with non-small cell lung cancer who harbor an epidermal growth factor receptor (EGFR) mutation initially respond well to EGFR-tyrosine kinase inhibitors (TKIs) eventually experience relapse. In this study, we have established a gefitinib-resistant cell line model by long-term exposure to gefitinib. We used originally gefitinib-sensitive lung cancer cell lines, namely PC9 and HCC827. We found that the expressions of both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells compared to those in PC9 naïve (PC9 na) cells. We found that proliferation of the PC9 GR cells was dependent on FGF2-FGFR1 pathway. Inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored the gefitinib sensitivity in PC9 GR cells. We propose FGF2-FGFR1 activation through autocrine loop is a novel mechanism of acquiring resistance to EGFR-TKIs and that this loop be targeted to overcome acquired resistance to EGFR-TKIs in a subset of NSCLC patients.

几乎所有表皮生长因子受体（EGFR）突变的非小细胞肺癌患者最初对EGFR-酪氨酸激酶抑制剂（TKIs）反应良好，最终都会复发。在本研究中，我们通过长期暴露于吉非替尼建立了吉非替尼耐药细胞系模型。我们最初使用吉非替尼敏感的肺癌细胞系，即PC9和HCC827。我们发现，与PC9 naïve （PC9 na）细胞相比，FGFR1和FGF2在耐吉非替尼（gefitinib resistant, PC9 GR）细胞中的表达均有所增加。我们发现PC9 GR细胞的增殖依赖于FGF2-FGFR1通路。用siRNA或FGFR抑制剂（PD173074）抑制FGF2或FGFR1可恢复PC9 GR细胞对吉非替尼的敏感性。我们提出通过自分泌环激活FGF2-FGFR1是获得EGFR-TKIs抗性的新机制，并且该环可以靶向克服NSCLC患者亚群中对EGFR-TKIs的获得性抗性。

项目成果

Aberrant DNA methylation and expression of mRNA in EGFR-mutant lung cancer cell line with long-term exposure to gefitinib

长期暴露于吉非替尼的 EGFR 突变肺癌细胞系中异常 DNA 甲基化和 mRNA 表达

• 发表时间: 2014
• 作者: A Hida;Y Ohsawa;S Kitamura;K Nakazaki;N Ayabe;Y Motomura;K Matsui;M Kobayashi;A Usui;Y Inoue;H Kusanagi;Y Kamei;K Mishima;梶原 千晶;Hideki Terai
• 通讯作者: Hideki Terai

Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure

长期暴露于吉非替尼的 EGFR 突变肺癌细胞系中 FGF2-FGFR1 通路的激活

• 发表时间: 2013
• 作者: Terai H;Soejima K;Naoki K;Yasuda H;Satomi R;Nakayama S;Yoda S;Ikemura S;Sato T;Ishioka K;Arai D;Ohgino K;Tani T;Kuroda A;Hamamoto J;Betsuyaku TTerai H;Soejima K;Naoki K;Yasuda H;Satomi R;Nakayama S;Yoda S;Ikemura S;Sato T;Ishioka K
• 通讯作者: Ishioka K

Kenzo Soejima, Katsuhiko Naoki et al. Activation of FGF2-FGFR1 pathway in EGFR-mutant lung cancer cell line with long-term gefitinib exposure

副岛贤三、直木胜彦等人

• 发表时间: 2013
• 作者: Terai H;Soejima KN;Yasuda H;Nakayama S;Hamamoto J;Arai D;Ishioka K;Ohgino K;Ikemura S;Sato T;Yoda S;Satomi R;Naoki K;Betsuyaku T.;Hideki Terai
• 通讯作者: Hideki Terai