Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathway.
Preclinical studies have shown the potential antitumour efficacy of monoclonal antibodies (MAbs) directed to the epidermal growth factor receptor (EGFR). In this report, we investigated the cytotoxic effects of the MAb matuzumab (EMD 72000) towards A431 cells and compared it to cetuximab. While cetuximab induced cell cycle arrest and inhibited A431 cell proliferation, matuzumab did not. Both MAbs inhibited growth factor induced EGFR, HER2 and AKT phosphorylation; however, only cetuximab inhibited ERK 1/2 phosphorylation. Taken together, the data indicate that each antibody may elicit different responses on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival. When combined, MAbs synergistically inhibited cell proliferation and induced EGFR down-regulation with a strong inhibition of ERK1/2 and AKT phosphorylation. In addition, both MAbs efficiently inhibited VEGF expression and induced ADCC, highlighting their therapeutic potential in vivo when used either as a single agent or in combination.
Meira
Debora Dummer
DD
Division of Clinical Research, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti, No. 37, 2° andar, Centro, Rio de Janeiro, Cep: 20231-050, RJ, Brazil; Departamento de Bioquímica, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
Nóbrega
Isabel
I
Division of Clinical Research, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti, No. 37, 2° andar, Centro, Rio de Janeiro, Cep: 20231-050, RJ, Brazil.
de Almeida
Vitor Hugo
VH
Division of Clinical Research, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti, No. 37, 2° andar, Centro, Rio de Janeiro, Cep: 20231-050, RJ, Brazil.
Mororó
Jânio S
JS
Division of Clinical Research, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti, No. 37, 2° andar, Centro, Rio de Janeiro, Cep: 20231-050, RJ, Brazil.
Cardoso
Alexander M
AM
Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Silva
Ricardo L A
RLA
Division of Clinical Research, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti, No. 37, 2° andar, Centro, Rio de Janeiro, Cep: 20231-050, RJ, Brazil.
Albano
Rodolpho M
RM
Departamento de Bioquímica, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
Ferreira
Carlos Gil
CG
Division of Clinical Research, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti, No. 37, 2° andar, Centro, Rio de Janeiro, Cep: 20231-050, RJ, Brazil. Electronic address: cferreira@inca.gov.br.
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D015536:Down-Regulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation; D011485:Protein Binding; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; C520777:matuzumab; D000068818:Cetuximab; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one