EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity.

TitleEGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity.
Publication TypeJournal Article
Year of Publication2007
AuthorsVikis, 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
JournalCancer Res
Volume67
Issue10
Pagination4665-70
Date Published2007 May 15
ISSN0008-5472
KeywordsAlleles, Animals, Cercopithecus aethiops, COS Cells, DNA, Neoplasm, ErbB Receptors, Genes, erbB-1, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Lung Neoplasms, Pedigree, Phosphorylation
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.

DOI10.1158/0008-5472.CAN-07-0217
Alternate JournalCancer Res.
PubMed ID17510392
PubMed Central IDPMC3460269
Grant ListR01ES012063 / ES / NIEHS NIH HHS / United States
R01CA058554 / CA / NCI NIH HHS / United States
R01 ES013340 / ES / NIEHS NIH HHS / United States
R01 CA093643 / CA / NCI NIH HHS / United States
P50CA70907 / CA / NCI NIH HHS / United States
U01 CA076293 / CA / NCI NIH HHS / United States
R01 CA080127 / CA / NCI NIH HHS / United States
R01CA099187 / CA / NCI NIH HHS / United States
ZIA BC010448-09 / NU / Intramural NIH HHS / United States
R01 CA058554 / CA / NCI NIH HHS / United States
P30 ES006096 / ES / NIEHS NIH HHS / United States
R01CA099147 / CA / NCI NIH HHS / United States
R01CA80127 / CA / NCI NIH HHS / United States
P30ES06096 / ES / NIEHS NIH HHS / United States
R01 CA099147 / CA / NCI NIH HHS / United States
R01CA093643 / CA / NCI NIH HHS / United States
P50 CA070907 / CA / NCI NIH HHS / United States
R01 CA099187 / CA / NCI NIH HHS / United States
R01ES013340 / ES / NIEHS NIH HHS / United States
R01 ES012063 / ES / NIEHS NIH HHS / United States
U01CA76293 / CA / NCI NIH HHS / United States
N01HG65404 / HG / NHGRI NIH HHS / United States
R03 CA077118 / CA / NCI NIH HHS / United States