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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in
Hidetaka Uramoto1, Kenji Sugio, Tsunehiro Oyama
1Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Abstract:
The protein-kinase family is the most frequently mutated gene family found in human cancer. Gefitinib, an ATP-competitive inhibitor of epidermal growth factor receptor (EGFR), also appears to be particularly effective in adenocarcinoma of the lung and in patients without smoking history. To determine whether lung tumors sensitive to gefitinib contained mutations within the tyrosine kinase (TK) domain of EGFR, we screened exons 18-23 of EGFR of tumors in 20 patients with non-small cell lung cancer (NSCLC) who had been treated with gefitinib. Nine (45%) tumors had TK domain mutations. All mutations were observed in adenocarcinoma. Seven (77.8%) of 9 cases with mutated types showed sensitivity to gefitinib, while no cases of 11 with wild type showed gefitinib sensitivity. Such mutations were more frequently observed in patients who had never smoked (5/8 or 62.5%) than in smokers (4/12 or 33.3%). The patients with mutations of EGFR to have a more favorable prognosis than those with wild type (p=0.033). These data show that adenocarcinomas from patients who had never smoked comprise a specific subset of patients with NSCLC sensitive to gefitinib treatment.
Insights
Gefitinib is effective for lung adenocarcinoma with EGFR mutations, particularly in never-smokers. These mutations predict a better prognosis for non-small cell lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The protein-kinase family is frequently mutated in human cancers.
- Gefitinib, an EGFR inhibitor, shows efficacy in lung adenocarcinoma, especially in never-smokers.
Purpose of the Study:
- To investigate EGFR tyrosine kinase (TK) domain mutations in gefitinib-sensitive non-small cell lung cancer (NSCLC).
Main Methods:
- Screening of EGFR exons 18-23 in tumors from 20 NSCLC patients treated with gefitinib.
- Correlation analysis of mutations with gefitinib sensitivity, smoking history, and prognosis.
Main Results:
- 45% of tumors harbored EGFR TK domain mutations, exclusively in adenocarcinomas.
- Mutations were associated with gefitinib sensitivity (77.8% of mutated cases) and a favorable prognosis (p=0.033).
- Mutations were more common in never-smokers (62.5%) than smokers (33.3%).
Conclusions:
- EGFR mutations define a subset of lung adenocarcinomas in never-smokers sensitive to gefitinib.
- EGFR mutation status is a predictive biomarker for gefitinib treatment in NSCLC.
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