Cetuximab insufficiently inhibits glioma cell growth due to persistent EGFR downstream signaling.
Overexpression and/or amplification of the epidermal growth factor receptor (EGFR) is present in 35-45% of primary glioblastoma multiforme tumors and has been correlated with a poor prognosis. In this study, we investigated the effect of cetuximab and intracellular signaling pathways downstream of EGFR, important for cell survival and proliferation. We show insufficient EGFR downregulation and competition with endogenous EGFR ligands upon cetuximab treatment. Dose-response experiments showed inhibition of EGFR phosphorylation without affecting two of the prominent downstream signaling pathways. Our results indicate that amplification and/or overexpression of EGFR is an unsatisfactory predictor for response to cetuximab.
Hasselbalch
Benedikte
B
Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Copenhagen, Denmark.
Lassen
Ulrik
U
Poulsen
Hans S
HS
Stockhausen
Marie-Thérése
MT
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D003513:Cycloheximide / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006258:Head and Neck Neoplasms / Q000473:pathology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D003513:Cycloheximide; D066246:ErbB Receptors; D000068818:Cetuximab