1. EGFR Mutations and Lung Cancer
- Author
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Greulich, Heidi, Chen, Tzu-Hsiu, Feng, Whei, Jänne, Pasi A, Alvarez, James V, Zappaterra, Mauro, Bulmer, Sara E, Frank, David A, Hahn, William C, Sellers, William R, and Meyerson, Matthew
- Subjects
Lung Neoplasms ,Patient Selection ,DNA Mutational Analysis ,Antineoplastic Agents ,Cell Biology ,Cancer: Lung ,Protein-Tyrosine Kinases ,respiratory tract diseases ,ErbB Receptors ,Oncology ,Humans ,Enzyme Inhibitors ,Research Article ,Cancer Biology - Abstract
Background Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. Methods and Findings Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. Conclusion Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies., Different EGFR mutations are associated with lung cancer. All of the classes can transform fibroblasts and lung epithelial cells, most are sensitive to erlotinib and gefininib, but exon 20 mutations are only sensitive to an irreversible EGFR inhibitor.
- Published
- 2005