PURPOSE: To establish whether cetuximab, a chimeric IgG1 antibody targeting 
epidermal growth factor receptor, has the potential to restore responsiveness to 
oxaliplatin in preclinical cancer models, as has been shown with irinotecan in 
irinotecan refractory metastatic colorectal cancer patients.
EXPERIMENTAL DESIGN: The effects of cetuximab and oxaliplatin, alone or in 
combination, were tested in vitro and in vivo using human colorectal cancer cell 
lines selected for oxaliplatin resistance, as well as parental control cell 
lines. Evaluations were made of subcutaneous xenograft tumor growth in nu/nu 
athymic mice, as well as activation of mitogen-activated protein kinase 
(extracellular signal-regulated kinase 1/2) and AKT, expression of DNA repair 
genes, density of apurinic/apyrimidinic DNA damage, and accumulation of 
platinum-DNA adducts in vitro.
RESULTS: Oxaliplatin + cetuximab efficacy in murine subcutaneous xenograft 
models was greater than that of monotherapies and independent of the 
responsiveness to oxaliplatin monotherapy. In vitro, cetuximab reduced 
expression of excision repair cross-complementation group 1 and XPF, which are 
key components of the nucleotide excision repair pathway involved in the 
excision of platinum-DNA adducts. In addition, cetuximab reduced expression of 
XRCC1, a component of the base excision repair pathway responsible for the 
repair of apurinic/apyrimidinic sites. Effects of cetuximab on DNA repair 
protein levels were downstream to effects on mitogen-activated protein kinase 
and AKT pathway activation. In line with effects on DNA repair protein 
expression, cetuximab increased the accumulation of platinum and 
apurinic/apyrimidinic sites on DNA during oxaliplatin treatment.
CONCLUSIONS: Cetuximab has the potential to salvage the benefits of oxaliplatin 
in oxaliplatin-resistant colorectal cancer patients by reducing DNA repair 
capacity.