Abstract

Gefitinib (ZD1839, Iressa(®)) is an orally active agent that inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR). Gefitinib has shown a high efficacy in patients with non-small cell lung carcinoma and specific mutations in the ATP-binding pocket of EGFR. These mutations, however, are extremely rare in squamous cell carcinomas of the head and neck (SCCHN). We previously showed that SCCHN cell lines with a heterozygous mutation (G/G→G/A) at nucleotide 2607 of EGFR are more sensitive to gefitinib than wild-type cell lines (79.5% higher IC(50)). To determine the relationship between the G/G and G/A genotypes, we assessed the EGFR gene copy number and the EGFR mRNA half-life in 16 different SCCHN cell lines. Fluorescence in situ hybridization showed that the EGFR copy number was significantly higher in the nine 2607G/A cell lines than in the seven 2607G/G cell lines (3.59±2.14 vs. 1.58±0.32 copies, a 2.27-fold difference). Similarly, the half life of EGFR mRNA was 2.24-fold higher in cell lines with the 2607G/A genotype than in those with wild-type. By contrast, the EGFR protein levels were inversely correlated with mRNA abundance. These findings suggest that sensitivity to gefitinib of cells with the heterozygous mutation (2607G/G→G/A) was closely associated with gene amplification, the prolongation of mRNA half-life and a decrease in EGFR protein.

Full Text
Published version (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