Differential Expression of DeltaEF1 Predicts Resistance to Erlotinib in HNSCC

OBJECTIVES: Epidermal growth factor receptor (EGFR) appears to be a logical theraputic target with increased tumor specificity for the treatment of head and neck squamous cell carcinoma (HNSCC). Erlotinib, a small molecule tyrosine kinase inhibitor, specifically inhibits aberrant EGFR signaling in HNSCC. We showed previously that expression of markers of epithelial to mesenchymal transition (EMT) predicts responsiveness to erlotinib in HNSCC in vitro. The purpose of this study was to identify the EMT inducing transcription factor that can be utilized as a molecular correlate of resistance to erlotinib in HNSCC cell lines.

EXPERIMENTAL METHODS: Cellular fractionation was utilized to separate cytoplasmic from nuclear portions in six HNSCC cell lines (3 erlotinib sensitive, 3 erlotinib resistant). Immunoblotting was used to detect expression levels of Delta EF1 transcription factor in each portion. Real time reverse transcriptase polymerase chain reaction was utilized to measure mRNA expression levels of Delta EF1 in those 6 HNSCC cell lines.

RESULTS: At both the protein and mRNA levels, Delta EF1 expression was significantly reduced or absent in erlotinib sensitive cell lines. Conversly, Delta EF1 expression was significantly elevated in erlotinib resistant cell lines with the highest level of expression detected in the most resistant cell line , 1386LN.

CONCLUSION:Expression of Delta EF1 transcription factor appears to directly correlate with resistance to EGFR-directed therapy in HNSCC cell lines. If validated in primary tumors, these results suggest that prospective evaluation of Delta EF1 expression status could be used as a means of identifying erlotinib-resistant tumors prior to therapy. Further studies will be performed utilizing tumor xenografts as well as primary patient tumor specimens to confirm this correlation. This research was supported by NIDCR training grant 5 T32 DEO 15355-02.