EGFR-Inhibition Enhances Apoptosis in Irradiated Human Head and Neck Xenograft Tumors Independent of Effects on DNA Repair

• Published in: Radiation research Vol. 180; no. 4; pp. 414 - 421
• Main Authors: Stegeman, H., Span, P. N., Cockx, S. C., Peters, J. P. W., Rijken, P. F. J. W., van der Kogel, A. J., Kaanders, J. H. A. M., Bussink, J.
• Format: Journal Article
• Language: English
• Published: United States The Radiation Research Society 01.10.2013; Radiation Research Society; Allen Press Inc
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Apoptosis - drug effects; Apoptosis - radiation effects; Cell Hypoxia - drug effects; Cell Hypoxia - radiation effects; Cell Line, Tumor; Cetuximab; Combined Modality Therapy; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair - drug effects; DNA Repair - radiation effects; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - radiation effects; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - radiotherapy; Humans; Hypoxia; Intracellular Signaling Peptides and Proteins - metabolism; Irradiation; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Phosphoproteins - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Receptor, Epidermal Growth Factor - antagonists & inhibitors; REGULAR ARTICLES; Space life sciences; Synergistic effect; Tumor Suppressor p53-Binding Protein 1; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0033-7587; 1938-5404
• DOI: 10.1667/RR3349.2

Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model.