Expression of insulin-like growth factor 1 receptor (IGF-1R) predicts poor responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer patients harboring activating EGFR mutations
Expression of insulin-like growth factor 1 receptor (IGF-1R) predicts poor responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer patients harboring activating EGFR mutations
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DOI：
10.1016/j.lungcan.2015.01.004
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发表时间：
2015-03-01
期刊：
影响因子：
5.3
通讯作者：
Kim, Tae-Jung
中科院分区：
文献类型：
--
作者：
Yeo, Chang Dong;Park, Ki Hoon;Kim, Tae-Jung
目的：胰岛素样生长因子1受体(IGF-1R)在非小细胞肺癌(NSCLC)中的表达与预后不良有关。IGF-1R途径激活下游靶点，绕过表皮生长因子受体(EGFR)信号的依赖，表皮生长因子受体(EGFR)介导对EGFR酪氨酸激酶抑制剂(TKIs)的抵抗。本研究的目的是确定IGF-1R的表达在EGFR激活突变的NSCLC患者接受EGFR-TKIs治疗后的预测作用。材料和方法：我们对62例存在激活的EGFR突变并接受TKI的NSCLC患者进行了回顾性研究。免疫组织化学染色检测IGF-1R、血管内皮生长因子(VEGF)和人表皮生长因子受体2(HER2)的蛋白表达。进行单变量和多变量分析，以确定与EGFR-TKIs反应相关的预测因素。结果：62例EGFR突变阳性患者中，26例表达IGF-1R，13例合并糖尿病。在多变量分析中，年轻年龄、鳞癌和IGF-1R的表达与EGFR-TKIs治疗后较短的PFS独立相关。表达胰岛素样生长因子-1R的患者与表达胰岛素样生长因子-1R的患者相比，对表皮生长因子受体-TKI的反应有显著缩短(9.1vs.20.1个月，p=0.005)。与非DM患者相比，接受一线EGFR-TKI治疗的13例DM患者表达IGF1R的可能性更大(p=0.001)，PFS时间更短(7.6月vs.18.6个月，p=0.005)。结论：IGF1R表达是EGFR-TKI激活的非小细胞肺癌患者对EGFR-TKI疗效的负面预测因素。此外，糖尿病患者在肿瘤组织中高表达IGF-1R，这与一线TKI治疗反应差有关。旨在克服EGFR-TKI耐药性的进一步研究也需要解决IGF-1R途径。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Objectives: Expression of insulin-like growth factor 1 receptor (IGF-1R) in non-small cell lung cancer (NSCLC) is associated with poor prognosis. The IGF-1R pathway activates downstream targets that bypass dependency in signals from the epidermal growth factor receptor (EGFR), which mediates resistance to EGFR tyrosine kinase inhibitors (TKIs). The aim of the present study was to determine the predictive role of IGF-1R expression in the response to EGFR-TKIs of NSCLC patients harboring activating EGFR mutations.Materials and methods: We retrospectively studied 62 NSCLC patients who had activating EGFR mutations and received TKIs. Protein expression of IGF-1R, vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) were measured by immunohistochemical staining. Univariate and multivariate analyses were performed to identify predictive factors associated with the responses to EGFR-TKIs. The relationship of progression-free survival (PFS) with IGF-1R expression and the presence of diabetes mellitus (DM) were examined.Results: Of 62 EGFR mutation positive patients, 26 expressed IGF-1R, and 13 had DM. In the multivariate analysis, young age, squamous cell carcinoma, and IGF-1R expression were independently associated with a shorter PFS after treatment with EGFR-TKIs. Patients expressing IGF-1R showed a significantly shorter PFS in response to EGFR-TKIs compared with those lacking IGF-1R expression (9.1 vs. 20.1 months, p = 0.005). The 13 patients with DM were more likely to express IGF-1R (p = 0.001) and had shorter PFS times when treated with first-line EGFR-TKIs (7.6 vs. 18.6 months, p = 0.005), compared with those without DM.Conclusion: IGF-1R expression was a negative predictive factor for a response to EGFR-TKIs in NSCLC patients harboring activating EGFR mutations. Moreover, patients with DM highly expressed IGF-1R in tumor tissues, which was associated with a poor response to first-line TKI therapy. Further studies aimed at overcoming EGFR-TKI resistance will need to also address IGF-1R pathways. (C) 2015 Elsevier Ireland Ltd. All rights reserved.