Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo

Molecular Cancer

Research

Jose M Lopez-Picazo¹  Alfonso Gurpide¹  Leticia Corrales²  Yi-Fan Hsu²  Daniel Ajona²  Ruben Pio³  Luis M Montuenga⁴ 

[1] Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain;Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain;Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain;Department of Biochemistry, School of Sciences, University of Navarra, Pamplona, Spain;Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain;Department of Histology, School of Medicine, University of Navarra, Pamplona, Spain;

关键词: Epidermal Growth Factor Receptor;    A549 Cell;    Cetuximab;    Complement Activation;    KRAS Mutation;   

DOI  :  10.1186/1476-4598-9-139

 received in 2010-01-15, accepted in 2010-06-07,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCetuximab, 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.ResultsEGFR-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.ConclusionsWe 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.

【 授权许可】

Unknown   
© Hsu et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.