EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines.
No mutation was found, which suggests that the biology of EGFR in gliomas is different from lung cancer and that this may be a factor in the resistance of glioblastomas to gefitinib.
In our series, female sex and bronchioloalveolar pathologic subtype predicted the presence of EGFR mutations in lung adenocarcinomas, and the high frequency of EGFR mutations supports the hypothesis that genetic backgrounds and/or environmental factors may affect the pathogenesis of certain lung cancers.
We recently reported findings demonstrating that a distinct class of EGFR inhibitors may overcome some mechanisms of secondary drug resistance in these tumors and may therefore be useful in treating lung cancer patients that initially responded to Iressa or Tarceva and eventually relapsed.
We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC.
Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non-small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers.
Genetic heterogeneity of EGFR suggests that the EGFR gene is unstable in established cancers and the heterogeneity may explain variable clinical responses of lung cancers to gefitinib.
As with other targeted agents, the key issues in the future will be to elucidate the molecular factors predicting a favorable response to the drugs as well as the rational integration with other targeted agents with activity in lung cancer, such as inhibitors of the epidermal growth factor receptor tyrosine kinase.
Studies have shown that mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are associated with response of lung cancer to gefitinib (Iressa, AstraZeneca Corp., Shanghai, China).
Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib.