Abstract
Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting. Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells. EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.
Highlights
Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival
We first sought to determine if EGFRvIII, a mutation correlated with increased tumorigenicity in glioblastoma, is present in HNSCC tumors
Quantitation of vascular endothelial growth factor (VEGF) expression by densitometry revealed that the level of VEGF was nearly doubled in HNSCC xenografts expressing the EGFRvIII (Fig. 3B; P = 0.04). This observation was confirmed by Western blot analysis showing increased VEGF expression in EGFRvIIItransfected xenografts from three representative nude mice (Fig. 3C). These results suggest that the expression of EGFRvIII in HNSCC contributes to increased growth in vitro and in vivo and is associated with elevated expression of VEGF
Summary
Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. EGFRvIII-expressing cells and vectortransfected controls were compared for growth rates in vitro and in vivo as well as chemotherapyinduced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Conclusions: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. We reported previously that >95% of HNSCCs express elevated EGFR levels compared with levels in normal mucosa from patients without cancer [4]. When combined with high-dose radiation in patients with locoregionally advanced HNSCC, the addition of C225 (EGFR-specific mAb) showed a statistically significant prolongation in overall. Clinical response to TKIs has failed to correlate with the promising antitumor effects seen in preclinical studies [11, 12], implicating persistent growth pathways despite blockade of wild-type EGFR (EGFRwt)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
