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EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity

¹ Washington University, St. Louis, Missouri; ² University of Texas Southwestern Medical Center, Dallas, Texas; ³ National Human Genome Research Institute, Bethesda, Maryland; ⁴ M. D. Anderson Cancer Center, Houston, Texas; ⁵ University of Cincinnati, Cincinnati, Ohio; ⁶ Mayo Clinic College of Medicine, Rochester, Minnesota; ⁷ National Cancer Institute, Rockville, Maryland; ⁸ University of Colorado, Denver, Colorado; ⁹ Karmanos Cancer Institute, Detroit, Michigan; ¹⁰ Medical University of Ohio, Toledo, Ohio; and ¹¹ Louisiana State University Health Science Center, New Orleans, Louisiana

Requests for reprints: Ming You, Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University, 660 Euclid Avenue, Box 8109, St. Louis, MO 63110. Phone: 314-362-9294; Fax: 314-362-9366; E-mail: youm{at}wustl.edu.

The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]

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