Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo.
Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo.
复制标题
DOI：
10.1186/1476-4598-9-139
复制
发表时间：
2010-06-07
期刊：
影响因子：
37.3
通讯作者：
Pio R
中科院分区：
文献类型：
--
作者：
Hsu YF;Ajona D;Corrales L;Lopez-Picazo JM;Gurpide A;Montuenga LM;Pio R
西妥昔单抗是一种靶向表皮生长因子受体（EGFR）的抗体，与化疗联合使用可延长晚期EGFR阳性非小细胞肺癌患者的生存期。在这项研究中，我们研究了补体激活在这种治疗药物的抗肿瘤机制中的作用。表达EGFR的肺癌细胞系能够结合西妥昔单抗并通过经典途径启动补体激活，而与EGFR的突变状态无关。这种激活导致补体成分沉积和补体介导的细胞死亡增加。在裸鼠A549肺癌细胞异种移植物中评价补体活化对西妥昔单抗体内活性的影响。A549细胞表达野生型EGFR并具有KRAS突变。西妥昔单抗对A549异种移植物的活性高度依赖于补体激活，因为补体耗竭完全消除了西妥昔单抗的抗肿瘤疗效。此外，西妥昔单抗活性显着较高的A549细胞中，补体抑制剂，因子H，基因下调。我们首次证明西妥昔单抗的体内抗肿瘤活性与补体介导的免疫应答有关。这些结果可能对开发新的基于西妥昔单抗的治疗策略和鉴定预测临床反应的标志物具有重要意义。
Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug. EGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated. We demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.
登录
查看更多内容
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
45.3
作者：
Giaccone, G;Herbst, RS;Johnson, DH
通讯作者：
Johnson, DH
DOI：
10.1093/jnci/djp280
发表时间：
2009-10-07
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Siena S;Sartore-Bianchi A;Di Nicolantonio F;Balfour J;Bardelli A
通讯作者：
Bardelli A
影响因子：
11.2
作者：
Natsume, Akito;In, Mika;Niwa, Rinpei
通讯作者：
Niwa, Rinpei
影响因子：
4.4
作者：
Ajona, Daniel;Hsu, Yi-Fan;Pio, Ruben
通讯作者：
Pio, Ruben