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EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer Res 2007 May 15;67(10):4665-70 PMID: 17510392 PMCID: PMC3460269

Pubmed ID

17510392

Abstract

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.

Author List

Vikis H, Sato M, James M, Wang D, Wang Y, Wang M, Jia D, Liu Y, Bailey-Wilson JE, Amos CI, Pinney SM, Petersen GM, de Andrade M, Yang P, Wiest JS, Fain PR, Schwartz AG, Gazdar A, Gaba C, Rothschild H, Mandal D, Kupert E, Seminara D, Viswanathan A, Govindan R, Minna J, Anderson MW, You M

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-34250329445   72 Citations

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
COS Cells
Cercopithecus aethiops
DNA, Neoplasm
ErbB Receptors
Genes, erbB-1
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Lung Neoplasms
Pedigree
Phosphorylation
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e