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

Abstract

Objective To investigate the expression of insulin-like growth factor 1(IGF-1)in epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)resistant non-small cell lung cancer(NSCLC)cell lines and patients,and to discuss the relevant clinical significance.Methods Levels of IGF-1were measured by ELISA kit in PC9,A549,H1975 cells and sera of EGFR-TKIs treated NSCLC patients;insulin-like growth factor-binding protein(IGFBP)expression was examined by Western blotting analysis and immunocytochemical method.Cell growth of NSCLC cells treated with gefitinib and BMS536924(antagonist of IGF-1receptor)was determined by MTT.The clinicopathological characteristics and survival period of 84 patients receiving EGFR-TKIs treatment were collected and their relationship with IGF-1expression was analyzed.Results It was found that IGF-1level in sensitive cell line PC9 was significantly higher than those in EGFR-TKIs resistant cell lines A549 and H1975(P0.05),while IGFBP expression was lower than those in A549 and H1975cells.Addition of BMS536924 of different concentrations significantly promoted the inhibitory effect of gefitinib against growth of A549 and H1975cells(P0.05).The patients with disease progression showed higher IGF-1expression than those without disease progression(P=0.052),while the patients with intrinsic resistance to EGFR-TKIs had significantly higher IGF-1level than those with acquired resistance(P=0.02).The patients with IGF-1negative expression had significantly longer survival than those with positive expression(P=0.002).Conclusion IGF-1expression is detected in EGFR-TKIs resistant NSCLC cell lines and patients,and antagonist of IGF-1receptor can restore the sensitivity to EGFR-TKIs.The expression of IGF-1is also a prognostic factor of NSCLC patients.