Mutant Epidermal Growth Factor Receptor (EGFRvIII) Contributes to Head and Neck Cancer Growth and Resistance to EGFR Targeting

Abstract

Purpose: 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. Experimental Design: 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 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. Results: 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. Conclusions: 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.

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

“…However, as witnessed in various tumour settings, use of such agents is not without undesirable consequences, and treatment can lead to toxicity and acquired drug resistance. Recently, expression of a tumour-specific constitutively active spliced variant of the receptor (EGFRvIII) was detected in 44% of a small cohort of HNSCCs and found to contribute to enhanced growth and resistance to wild-type EGFRtargeting antibodies (Sok et al, 2006). Altogether these events highlight the therapeutic advantage that targeting multiple components of the EGFR/Src/cortactin axis could represent.…”

A genetic view of laryngeal cancer heterogeneity

“…EGFRvIII is seen in cells that overexpress wild-type EGFR suggesting that mutations are a later event caused by rapid proliferation induced by EGFR overexpression. 58 …”

Genomics of Squamous Cell Lung Cancer

“…This variant is characterized by the deletion of exons 2-7 that prevents ligand binding but confers constitutively active kinase activity to the receptor [103]. Decreased response to therapy with cisplatin and cetuximab was reported in head and neck SQCCs (HNSCCs) harboring this variant [104]. Evidence from a cell line study also suggests that EGFR vIII harboring tumors are relatively resistant (Ͼ40 fold more resistant compared with L858R variant) to gefitinib and erlotinib [102].…”