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


RESULTS
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.


CONCLUSIONS
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.
Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain.
Yi-Fan
YF
Hsu
Daniel
D
Ajona
Leticia
L
Corrales
Jose M
JM
Lopez-Picazo
Alfonso
A
Gurpide
Luis M
LM
Montuenga
Ruben
R
Pio
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003167:Complement Activation / Q000187:drug effects*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000032:analysis; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab