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In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation.
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Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In analyzing the tumor from a 33-year-old male never-smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18-25 kinase domain duplication (EGFR-KDD). Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKI). EGFR mutations are found in 10% to 35% of lung adenocarcinomas. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. 9 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.Department of Chemistry, Vanderbilt University Medical Center, Nashville, Tennessee. 8 Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee.7 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.6 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.5 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.4 Foundation Medicine Inc., Cambridge, Massachusetts.Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee. 3 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee. 2 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee.1 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.we try to give more, this is a very big work, but it goes to the glory of God.
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