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

Mol Cancer. 2010 Jun 7;9:139. doi: 10.1186/1476-4598-9-139.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Cell Line, Tumor
  • Cetuximab
  • Complement Activation / drug effects*
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology*
  • Mice
  • Mice, Nude
  • Mutation
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Messenger / analysis
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Cetuximab