Correlation of HER1/EGFR expression and degree of radiosensitizing effect of the HER1/EGFR-tyrosine kinase inhibitor erlotinib.
Correlation of HER1/EGFR expression and degree of radiosensitizing effect of the HER1/EGFR-tyrosine kinase inhibitor erlotinib.
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发表时间：
2005-12
影响因子：
1.4
通讯作者：
Jae-Chul Kim;M. Ali;A. Nandi;P. Mukhopadhyay;H. Choy;C. Cao;D. Saha
中科院分区：
文献类型：
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作者：
Jae-Chul Kim;M. Ali;A. Nandi;P. Mukhopadhyay;H. Choy;C. Cao;D. Saha
表皮生长因子受体 (HER1/EGFR) 介导的信号转导途径在细胞对电离辐射的反应中非常重要。癌细胞上 HER1/EGFR 的高表达可能有助于放射抗性。在这项临床前研究中，我们评估了小分子 HER1/EGFR 抑制剂厄洛替尼在具有不同 HER1/EGFR 表达的三种人类癌细胞系——A431（极高表达）、H157（中度表达）和 H460（低表达）中的放射增敏作用。我们的结果表明，A431 的辐射抗性最强，而 H460 的辐射敏感性最强。然而，A431 细胞对厄洛替尼最敏感（IC50 = 300 nM），H460 细胞耐药性最强（IC50 = 8 µM）。 H157 对辐射和厄洛替尼具有中等敏感性 (IC50 = 3 microM)。使用 300 nM 厄洛替尼时，A431、H157 和 H460 的放射剂量增强比 (DER) 分别为 1.40、1.17 和 1.04。使用 300 nM 厄洛替尼治疗 24 小时，A431、H157 和 H460 的 G1 期阻滞分别增加了 18.6%、2.0% 和 4.8%。仅在 A431 细胞中，辐射增强了厄洛替尼诱导的细胞凋亡。总之，HER1/EGFR 高表达可能导致厄洛替尼联合放疗的高度放射增敏作用。厄洛替尼诱导的放射增敏程度与 HER1/EGFR 表达以及人表皮生长因子受体 (HER1/EGFR) 的自身磷酸化成正比。
Epidermal growth factor receptor (HER1/EGFR)-mediated signal transduction pathways are important in cellular response to ionizing radiation. High HER1/EGFR expression on cancer cells may contribute to radioresistance. In this pre-clinical study, we evaluated the radiosensitizing effect of erlotinib, a small molecule HER1/EGFR inhibitor in three human cancer cell lines with different HER1/EGFR expression--A431 (very high expression), H157 (moderate expression) and H460 (low expression). Our results demonstrated that A431 was the most radioresistant, while H460 was the most radiosensitive. However, A431 cells were the most sensitive to erlotinib (IC50 = 300 nM) and H460 cells the most resistant (IC50 = 8 microM). H157 had intermediate sensitivity to radiation and erlotinib (IC50 = 3 microM). With 300 nM erlotinib, the radiation dose enhancement ratios (DER) were 1.40, 1.17 and 1.04 in A431, H157 and H460, respectively. Treatment with erlotinib for 24 hr at 300 nM increased G1 arrest by 18.6, 2.0 and 4.8% in A431, H157 and H460, respectively. Erlotinib-induced apoptosis was augmented by radiation in A431 cells only. In conclusion, high HER1/EGFR expression may result in a high degree of radiosensitization with erlotinib combined with radiation. The extent of erlotinib-induced radiosensitization was proportional to HER1/EGFR expression, as well as autophosphorylation of the human epidermal growth factor receptor (HER1/EGFR).