胰岛素样生长因子1在非小细胞肺癌EGFR-TKIs耐药机制中的作用

目的探讨胰岛素样生长因子1(IGF-1)在表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药的非小细胞肺癌(NSCLC)细胞株和患者中的表达和临床意义。方法 ELISA法检测PC9、A549、H1975细胞和患者血清IGF-1水平,蛋白质印迹和免疫细胞化学法检测细胞中胰岛素样生长因子结合蛋白(IGFBP)的表达;MTT法检测吉非替尼和IGF-1受体拮抗剂BMS536924处理后的细胞增殖;收集84例接受EGFR-TKIs治疗患者的临床资料,分析IGF-1表达与临床病理特征和生存期的相关性。结果同吉非替尼敏感细胞株PC9相比,耐药细胞株H1975和A549中IGF-1表达增加(P<0.05),IGFBP表达降低;加入不同浓度的BMS536924可促进吉非替尼对耐药细胞株的增殖抑制(P<0.05)。在接受EGFR-TKIs治疗的患者中,疾病进展者的IGF-1水平较疾病控制者有所增高(P=0.052);原发性耐药者较获得性耐药者的IGF-1水平升高(P=0.02)。IGF-1表达阴性患者的生存期高于阳性患者(P=0.002)。结论 IGF-1在耐药NSCLC细胞株及患者血清中均有高表达,使用IGF-1R拮抗剂可逆转耐药细胞对EGFR-TKIs的反应;IGF-1表达与患者预后相关。

Role of insulin-like growth factor 1 in drug resistance to EGFR-TKIs in non-small cell lung cancer

Objective To investigate the expression of IGF 1 in EGFR-TKIs resistant NSCLC cell lines and patients. The clinical significance of IGF 1 expression was also studied. Method Level of IGF 1 in PC 9, A549, H1975 cell lysates and serum from EGFR-TKIs treated patients were measured by Elisa kit. IGFBP expression was detected by western blot and IHC. Cell growth of cells treated with gefitinib and BMS536924 was determined by MTT. The clinicopathological characteristics and survival times of 84 patients with EGFR-TKIs treatment were collected. Their relationship with IGF 1 expression was analyzed. Results We found increased IGF1 level and decreased IGFBP expression in EGFR-TKIs resistant cell lines A549 and H1975 compared with sensitive cell line PC9(p<0.05); Cell growth was inhibited by BMS536924 combined with gefitinib in A549 and H1975 cell lines(p<0.05).The patients with disease progression showed higher IGF 1 expression than those with disease control(p=0.052),while the patients with intrinsic resistance to EGFR-TKIs had significantly higher IGF 1 level than those with acquired resistance(p=0.02). The patients with IGF 1 negative expression showed longer survival time than those with positive expression(p=0.002). Conclusion Increased IGF 1 expression was detected in EGFR-TKIs resistant cell lines and patients. The antagonist to IGF-1R could restore EGFR-TKIs sensitivity. The expression of IGF 1 in NSCLC patients was a prognostic factor.