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Gefitinib-sensitizing mutation in esophageal carcinoma cell line Kyse450
Mingzhou Guo1, Shuang Liu, James G Herman
1The Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Purpose:
The sensitivity of lung cancer to gefitinib has been found to be associated with mutations at the tyrosine kinase domain of epidermal growth factor receptor (EGFR), yet similar observations are not available in other solid tumors. We recently identified mutations in the EGFR kinase domain in primary esophageal carcinoma. The purpose of this study was to investigate if they are gefitinib-sensitizing EGFR mutations.
Experimental Design:
We identified a missense mutation in the EGFR kinase domain, EGRFS7681, in the esophageal cancer cell line Kyse450. The sensitivity of this cell line to gefitinib was compared to an esophageal cancer cell line with wildtype EGFR, TE8, and to a lung cancer cell line, H358, known to be resistant to gefitinib. The effect of EGFR(S7681) mutation on cell growth and apoptosis was assessed.
Results:
As demonstrated by in vitro proliferation assay, this mutation sensitized Kyse450 cells to gefitinib. The observation of down regulation of the phosphorylated pAKT indicated gefitinib induced Kyse450 cells apoptosis via inhibition of EGFR activity
Conclusions:
While more primary esophageal tumors remain to be screened for the mutations at the tyrosine kinase domain of EGFR, current observation implies that gefitinib may be worth further investigation for treatment of esophageal cancers.
Insights
A specific mutation in the epidermal growth factor receptor (EGFR) kinase domain sensitizes esophageal cancer cells to gefitinib, suggesting potential for this targeted therapy in esophageal cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gefitinib sensitivity in lung cancer is linked to epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations.
- Similar EGFR mutations have been identified in primary esophageal carcinoma.
- The role of these mutations in gefitinib sensitivity in esophageal cancer remains unexplored.
Purpose of the Study:
- To investigate if identified mutations in the EGFR kinase domain of esophageal carcinoma are sensitizing to gefitinib.
- To assess the impact of the EGFR(S7681) mutation on esophageal cancer cell growth and apoptosis.
Main Methods:
- Identified a missense mutation, EGFR(S7681), in the esophageal cancer cell line Kyse450.
- Compared gefitinib sensitivity of Kyse450 cells (mutated EGFR) to TE8 (wildtype EGFR) and H358 (resistant EGFR) cell lines.
- Assessed the effect of the EGFR(S7681) mutation on cell proliferation and apoptosis.
Main Results:
- The EGFR(S7681) mutation sensitized Kyse450 cells to gefitinib, as shown by in vitro proliferation assays.
- Gefitinib induced apoptosis in Kyse450 cells, indicated by downregulation of phosphorylated pAKT.
- This suggests gefitinib inhibits cancer cell growth via EGFR activity.
Conclusions:
- The EGFR(S7681) mutation confers gefitinib sensitivity in esophageal cancer cells.
- Gefitinib warrants further investigation as a potential treatment for esophageal cancers harboring EGFR kinase domain mutations.
- Screening of primary esophageal tumors for EGFR mutations is recommended.
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