Correspondence

Gefitinib-Sensitizing Mutations in Esophageal Carcinoma

N Engl J Med 2006; 354:2193-2194May 18, 2006

Article

To the Editor:

The sensitivity of lung cancer to gefitinib has been found to be associated with mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR),1-3 yet similar observations are not available for other solid tumors.4 We investigated whether gefitinib-sensitizing mutations in the EGFR gene were present in human esophageal tumors.

DNA that was isolated from fresh-frozen tissue from 87 specimens of primary esophageal carcinoma — which included 20 specimens of dysplasia, 10 of primary esophageal adenocarcinoma, and 57 of primary esophageal squamous-cell carcinoma — were screened for mutations in EGFR gene exons 18 through 21 by direct polymerase-chain-reaction sequencing from both directions. We also sequenced exons 18 through 21 of the EGFR gene in 17 human esophageal tumor–derived cell lines at both DNA and messenger RNA (mRNA) levels (Figure 1Figure 1Mutation in the EGFR Gene in the Kyse450 Esophageal Carcinoma Cell Line.). We identified an EGFR A743P mutation in 1 of 10 specimens of primary esophageal adenocarcinoma, an EGFR S768I mutation in the Kyse450 esophageal squamous-cell carcinoma cell line, and an EGFR E872 GAA-to-TAA mutation causing truncation of EGFR and two silent mutations at EGFR G873 (GGA/GGT) and P753 (CCG/CCA) in 57 primary esophageal squamous-cell carcinomas. No mutation was detected in any of the 20 specimens of dysplasia screened.

Previous work unequivocally demonstrated that gefitinib inhibits tyrosine phosphorylation of EGFR S768I more effectively than that of wild-type EGFR.5 On the basis of this result, we anticipated that Kyse450 cells, which harbor the EGFR S768I mutant receptor, would exhibit increased sensitivity to gefitinib. Indeed, in vitro proliferation assays revealed that the EGFR S768I mutation sensitized Kyse450 cells to gefitinib, as compared with cells expressing the wild-type receptor. Our observation of increased sensitivity to gefitinib-dependent growth inhibition in cultured Kyse450 cells harboring the EGFR S768I mutation differs from the finding reported by Chen et al.5 that gefitinib promoted the proliferation of 32D cells overexpressing ectopic EGFR S768I. It is important to point out that unlike the heterozygous EGFR gene mutations found in patients with non–small-cell lung cancer that are clinically sensitive to gefitinib, 32D cells do not express endogenous wild-type EGFR. Another explanation of the discrepancy might be the difference between the genetic backgrounds of the host cells. Taken together, our finding of the gefitinib-sensitizing mutations in EGFR genes suggests that although more primary esophageal tumors remain to be screened for mutations in the tyrosine kinase domain of EGFR, gefitinib may be worth further investigation as a potential therapeutic intervention for esophageal cancers.

Mingzhou Guo, M.D., Ph.D.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231

Shuang Liu, M.D.
Peking University Health Science Center, Beijing 100083, China

Fengmin Lu, M.D., Ph.D.
Peking University Health Science Center, Beijing 100083, China
lu.fengmin@bjmu.edu.cn

Dr. Lu reports having received a research grant from AstraZeneca.

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