EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks.
EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks.
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DOI：
10.1158/0008-5472.can-11-0213
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发表时间：
2011-10-01
期刊：
影响因子：
11.2
通讯作者：
Willers H
中科院分区：
文献类型：
--
作者：
Wang M;Morsbach F;Sander D;Gheorghiu L;Nanda A;Benes C;Kriegs M;Krause M;Dikomey E;Baumann M;Dahm-Daphi J;Settleman J;Willers H
抑制表皮生长因子受体（EGFR）使非小细胞肺癌（NSCLC）细胞对电离辐射敏感的机制仍知之甚少。我们着手研究酪氨酸激酶抑制剂厄洛替尼和单克隆抗体西妥昔单抗在含有野生型p53的NSCLC细胞中的放射增敏作用。出乎意料的是，EGFR抑制导致明显的细胞衰老，但在体外和体内照射细胞的凋亡。衰老完全依赖于野生型p53，并与细胞数量的减少以及受损的克隆性辐射存活相关。对另外10个NSCLC细胞系的研究表明，衰老是45%细胞系中放射增敏的主要机制，不仅发生在具有野生型p53的细胞中，而且发生在具有突变型p53的细胞中，在突变型p53的细胞中，衰老与p16的诱导相关。有趣的是，衰老和放射增敏与残余辐射诱导的DNA双链断裂的增加有关，而与p53/p16状态无关。EGFR抑制的这种作用至少部分由MEK-ERK通路的破坏介导。因此，我们的数据表明，不同遗传背景的厄洛替尼或西妥昔单抗的放射增敏作用具有共同的机制。我们的研究结果还表明，能够捕获与衰老相关的初始增殖延迟的检测方法应该有助于筛选大细胞系组，以识别EGFR抑制剂介导的放射增敏的基因组生物标志物。
The mechanisms by which inhibition of the epidermal growth factor receptor (EGFR) sensitizes non-small cell lung cancer (NSCLC) cells to ionizing radiation remain poorly understood. We set out to characterize the radiosensitizing effects of the tyrosine kinase inhibitor erlotinib and the monoclonal antibody cetuximab in NSCLC cells that contain wild-type p53. Unexpectedly, EGFR inhibition led to pronounced cellular senescence but not apoptosis of irradiated cells both in-vitro and in-vivo. Senescence was completely dependent on wild-type p53 and associated with a reduction in cell number as well as impaired clonogenic radiation survival. Study of ten additional NSCLC cell lines revealed that senescence is a prominent mechanism of radiosensitization in 45% of cell lines and occurs not only in cells with wild-type p53 but also in cells with mutant p53 where it is associated with an induction of p16. Interestingly, senescence and radiosensitization were linked to an increase in residual radiation-induced DNA double-strand breaks irrespective of p53/p16 status. This effect of EGFR inhibition was at least partially mediated by disruption of the MEK-ERK pathway. Thus, our data indicate a common mechanism of radiosensitization by erlotinib or cetuximab across diverse genetic backgrounds. Our findings also suggest that assays that are able to capture the initial proliferative delay that is associated with senescence should be useful for screening large cell line panels to identify genomic biomarkers of EGFR inhibitor-mediated radiosensitization.