Overcoming epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)-resistance in lung cancer through PI3-kinase pathway

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）在EGFR突变的肺癌患者的治疗中具有重要作用。但许多患者最终在一年内恶化（成为“耐药”）。本研究以肺癌细胞株为研究对象，阐明了成纤维细胞生长因子（FGF）及其受体（FGFR）与肺癌细胞对EGFT-TKI耐药的关系。使用临床标本，FGF 9高表达与肺癌患者的不良预后相关。FGF在肺上皮细胞中过表达可诱导转化，并加速免疫缺陷小鼠的肿瘤形成。FGFR抑制剂阻断了肿瘤形成。通过细胞系和临床标本的研究，我们全面揭示了FGF/FGFR通路在肺癌的预后、肿瘤形成和耐药中的重要作用，提示FGF/FGFR通路有可能成为肺癌的药物靶点。

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have great effect in the treatment of lung cancer patients with EGFR mutation. But many of the patients eventually get worsened (become 'resistance') within one year. It is important to overcome the 'EGFR-TKI-resistance'.Using lung cancer cell lines, we had elucidated that fibroblast growth factors (FGFs) and receptors (FGFRs) had related to the EGFT-TKI resistance. Using clinical specimens, high FGF9 expression is related to poor prognosis in lung cancer patients. Overexpression of FGF in lung epithelial cell induced transformation, and the tumor formation in immune-deficient mouse was accelerated. FGFR-inhibitor blocked that tumor formation. Using cell lines and clinical specimens, we have comprehensively revealed that FGF/FGFR pathway has an important role in prognosis, tumor formation, and resistance in lung cancer, suggesting that FGF/FGFR pathway can be possible drug target.