Laboratory of Radiobiology & Experimental Radiooncology, Germany.
Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany.
Radiother Oncol. 2015 Apr;115(1):120-7. doi: 10.1016/j.radonc.2015.02.018. Epub 2015 Mar 18.
How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects.
We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model.
When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition.
For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation.
表皮生长因子受体 (EGFR) 抑制如何诱导细胞放射增敏以及由此增加肿瘤控制率仍存在争议。由于 EGFR 主要调节细胞周期和增殖，我们研究了 EGFR 抑制引起的 G1 期阻滞是否有助于产生这些效应。
我们分析了人非小细胞肺癌 (NSCLC) 细胞系，包括野生型 (wt) 和 p53 突变型 (A549、H460、vs. H1299、H3122) 和 HCT116 细胞 (p21wt 和阴性)。用 BIBX1382BS、厄洛替尼或西妥昔单抗抑制 EGFR；用 siRNA 敲低 p21。分析的功能终点包括细胞信号转导、增殖、G1 期阻滞、细胞存活以及使用 A549 肿瘤模型的肿瘤控制率。
当与 IR 联合使用时，EGFR 抑制增强了辐射诱导的永久性 G1 期阻滞，但仅在具有完整 p53/p21 信号的细胞中。这种 G1 期阻滞的增加总是与增强的细胞放射敏感性相关。引人注目的是，当细胞被重新刺激时，这种效应被消除，表明休眠的开始。与此一致的是，用分割放疗和 EGFR 抑制治疗 A549 肿瘤时，肿瘤控制率仅略有非显著增加。
对于 NSCLC 细胞，EGFR 抑制增加放射敏感性是由于 G1 期阻滞增强所致。然而，这种效应并没有导致肿瘤控制率的改善，因为细胞可以通过重新刺激从这种阻滞中释放出来。
