Investigation of the mechanism of gefitinib resistance by comprehensive genetic analysis

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。

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.