Department of Medicine/Medical Oncology, University of Colorado Cancer Center, UC Denver, 12801 E 17th Ave, Mail Stop 8177, Aurora, CO 80045, USA.
Cell Oncol (Dordr). 2013 Jul;36(4):277-88. doi: 10.1007/s13402-013-0133-9. Epub 2013 Apr 26.
The insulin-like growth factor-1 receptor (IGF-1R) pathway is known to play a role in the acquisition of resistance to epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, its exact role in TKI resistance has so far remained unclear. Here, we interrogated the hypothesis that the IGF-1R may serve as a biomarker for, and may play a role in, intrinsic resistance to the EGFR-specific TKI gefitinib in NSCLC.
Total-IGF-1R and phosphorylated (p)-IGF-1R expression levels were related to gefitinib sensitivity in 23 NSCLC cell lines. This sensitivity was re-evaluated after knocking down IGF-1R expression and after IGF-1R up-regulation through exogenous IGF-1 expression. The utility of IGF-1R expression as a predictive biomarker was also evaluated by immunohistochemistry (IHC) in 98 primary NSCLC samples from patients treated with gefitinib.
Seventeen of the cell lines tested were resistant to gefitinib, whereas 3 cell lines were sensitive. The three remaining cell lines showed intermediate values. Thirteen resistant cell lines were found to be positive for total-IGF-1R expression, while all the sensitive cell lines were negative, resulting in a positive predictive value (PPV) of 81% for total-IGF-1R to predict resistance. Seven resistant cell lines exhibited high p-IGF-1R levels, whereas all 3 sensitive cell lines were negative for p-IGF-1R, resulting in a PPV of 100% for p-IGF-1R to predict resistance. Neither a knock-down of IGF-1R expression nor an activation of the IGF1-R pathway through exogenous IGF-1 expression affected gefitinib sensitivity. In primary NSCLC tissues, IGF-1R expression was found to be significantly higher in patients with progressive disease, i.e., showing gefitinib resistance, as compared to those with a complete or partial response.
IGF-1R acts as a predictor for resistance to gefitinib in NSCLC cell lines and NSCLC patients, but does not seem to play a role in the intrinsic resistance to this drug. High total-IGF-1R and p-IGR-1R levels may predict such a resistance. Since the underlying mechanism does not appear to be related to proliferation induction, alternative pathways should be explored.
已知胰岛素样生长因子-1 受体（IGF-1R）途径在非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）特异性酪氨酸激酶抑制剂（TKI）获得耐药性中起作用。然而，其在 TKI 耐药性中的确切作用迄今仍不清楚。在这里，我们探讨了这样一种假设，即 IGF-1R 可能作为生物标志物，并在 NSCLC 中对 EGFR 特异性 TKI 吉非替尼的内在耐药性中发挥作用。
在 23 种 NSCLC 细胞系中，总 IGF-1R 和磷酸化（p）-IGF-1R 表达水平与吉非替尼敏感性相关。通过敲低 IGF-1R 表达和通过外源性 IGF-1 表达上调 IGF-1R 后，重新评估了这种敏感性。还通过对接受吉非替尼治疗的 98 例 NSCLC 患者的 98 例原发性 NSCLC 样本的免疫组织化学（IHC）评估了 IGF-1R 表达作为预测生物标志物的效用。
在测试的 17 种细胞系中，有 17 种对吉非替尼耐药，而有 3 种细胞系敏感。其余三种细胞系表现出中间值。发现 13 种耐药细胞系的总 IGF-1R 表达阳性，而所有敏感细胞系均为阴性，因此总 IGF-1R 对预测耐药性的阳性预测值（PPV）为 81%。7 种耐药细胞系表现出高 p-IGF-1R 水平，而所有 3 种敏感细胞系均为 p-IGF-1R 阴性，因此 p-IGF-1R 对预测耐药性的阳性预测值（PPV）为 100%。敲低 IGF-1R 表达或通过外源性 IGF-1 表达激活 IGF1-R 途径均不影响吉非替尼的敏感性。在原发性 NSCLC 组织中，与完全或部分反应的患者相比，疾病进展的患者（即对吉非替尼耐药）的 IGF-1R 表达明显更高。
IGF-1R 可作为 NSCLC 细胞系和 NSCLC 患者对吉非替尼耐药的预测因子，但似乎在该药物的内在耐药性中不起作用。高总 IGF-1R 和 p-IGR-1R 水平可能预测这种耐药性。由于潜在的机制似乎与增殖诱导无关，因此应探索替代途径。
