Cetuximab: from bench to bedside.
Cetuximab (IMC-C225, Erbitux ImClone Systems Inc, New York, NY) is a recombinant, human/mouse chimeric monoclonal antibody (MAb) that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) as well as other ligands. Cetuximab binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases and their associated downstream signalling (MAPK, PI3K/Akt, Jak/Stat pathways) resulting in inhibition of many cellular processes such as induction of apoptosis, cell growth, decreased Matrix Metallo-Proteinase (MMPs) and vascular endothelial growth factor (VEGF) production. Cetuximab is also able to display cytotoxic effect through antibody-dependent cellular cytotoxicity (ADCC). In vitro and in vivo experiments elucidated a wide range of biological properties attributed to cetuximab, these include: direct inhibition of EGFR tyrosine kinase activity, inhibition of cell cycle progression, inhibition of angiogenesis, invasion and metastatization processes, activation of pro-apoptotic molecules and synergic cytotoxicity effect with chemotherapy and radiotherapy. Several studies have shown cetuximab is able to inhibit growth of EGFR-expressing tumor cells in vitro as well as in nude mice bearing xenografts of human cancer cell lines. Moreover, numerous clinical trials demonstrated cetuximab efficacy in different tumor types and it is approved by Food and Drugs Administration (FDA) for use in the treatment of metastatic colorectal cancer (mCRC) as single agent or in combination with chemotherapy, for locally/regionally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy, and as monotherapy for recurrent/metastatic HNSCC after failing platinum-based chemotherapy. This review will illustrate pre-clinical and clinical data on biological properties of cetuximab focusing on the predictive markers of clinical response to this drug.
Vincenzi
Bruno
B
Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy. b.vincenzi@unicampus.it
Zoccoli
Alice
A
Pantano
Francesco
F
Venditti
Olga
O
Galluzzo
Sara
S
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab