Effect of epidermal growth factor receptor inhibitor class in the treatment of head and neck cancer with concurrent radiochemotherapy in vivo.
OBJECTIVE
To optimally integrate epidermal growth factor receptor (EGFR) inhibitors into the clinical treatment of head and neck cancer, two important questions must be answered: (a) does EGFR inhibition add to the effects of radiochemotherapy, and (b) if so, which method of inhibiting EGFR is superior (an EGFR antibody versus a small molecule tyrosine kinase inhibitor)? We designed an in vivo study to address these questions.


METHODS
Nude mice with UMSCC-1 head and neck cancer xenografts received either single, double, or triple agent therapy with an EGFR inhibitor (either cetuximab or gefitinib), gemcitabine, and/or radiation for 3 weeks. Tumor volumes and animal weights were measured for up to 15 weeks. Immunoblotting and immunofluorescent staining were done on tumors treated with either cetuximab or gefitinib alone.


RESULTS
The addition of an EGFR inhibitor significantly delayed the tumor volume doubling time, from a median of 40 days with radiochemotherapy (gemcitabine and radiation) alone, to 106 days with cetuximab and 66 days with gefitinib (both P < 0.005). Cetuximab resulted in significantly less weight loss than gefitinib. Immunoblot analysis and immunofluorescent staining of tumors show that although levels of phosphorylated AKT and extracellular signal-regulated kinase were decreased similarly in response to cetuximab or gefitinib, cetuximab caused prolonged suppression of pEGFR, pSTAT3, and Bcl(XL) compared with gefitinib.


CONCLUSIONS
EGFR inhibition, particularly with cetuximab, improves the effectiveness of radiochemotherapy in this model of head and neck cancer. The correlation of response with prolonged suppression of EGFR, STAT3, and Bcl(XL) offers the possibility that these may be candidate biomarkers for response.
Feng
Felix Y
FY
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Lopez
Carlos A
CA
Normolle
Daniel P
DP
Varambally
Sooryanarayana
S
Li
Xiaoxin
X
Chun
Patrick Y
PY
Davis
Mary A
MA
Lawrence
Theodore S
TS
Nyati
Mukesh K
MK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000627:therapeutic use; D051381:Rats; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D003841:Deoxycytidine; D066246:ErbB Receptors; D000068818:Cetuximab; D000077156:Gefitinib; D000093542:Gemcitabine