Different proteome pattern of epidermal growth factor receptor-positive colorectal cancer cell lines that are responsive and nonresponsive to C225 antibody treatment.
The monoclonal antibody C225 directed against the epidermal growth factor receptor (EGFR) blocks downstream mitogenic signaling and is effective in patients with advanced colorectal cancer. Clinical data, however, suggest the presence of primary and secondary resistance mechanisms that are hardly understood. To define proteins involved in EGFR-triggered growth regulation and potential resistance mechanisms, we characterized the proteome profile of two colorectal cancer cell lines with a high expression of functional EGFR but a different response to treatment with C225. In Caco-2 and HRT-18, a complete saturation of EGFR was achieved after incubation with C225; whereas Caco-2 showed inhibition of proliferation, growth of HRT-18 was not suppressed. Using two-dimensional electrophoresis and subsequent mass spectrometry, we identified 14 proteins differentially expressed in both cell lines. All proteins are involved in metabolic pathways and malignant growth. Expression of enzymes such as ubiquitin carboxyl-terminal hydrolase isozyme 1, glutathione S-transferase P, and chloride intracellular channel protein 1 does not seem to interfere with the antiproliferative effect of anti-EGFR antibody. On the other hand, expression of proteins such as fatty acid binding protein and heat shock protein 27 might constitute strong antiapoptotic effects contributing to the nonresponse of HRT-18 to C225 treatment. Proteome-based investigations can help us better understand the complex protein interactions involved in EGFR signaling and its blockage by therapeutic monoclonal antibodies.
Skvortsov
Sergej
S
Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria.
Sarg
Bettina
B
Loeffler-Ragg
Judith
J
Skvortsova
Ira
I
Lindner
Herbert
H
Werner Ott
Helmut
H
Lukas
Peter
P
Illmensee
Karl
K
Zwierzina
Heinz
H
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D009363:Neoplasm Proteins / Q000378:metabolism; D020543:Proteome; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D020543:Proteome; D066246:ErbB Receptors; D000068818:Cetuximab