title: EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity.
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.
authors.affiliation: Washington University, St. Louis, Missouri, USA.
authors.forename: Haris
authors.initials: H
authors.lastname: Vikis
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.forename: Daolong
authors.initials: D
authors.lastname: Wang
authors.forename: Yian
authors.initials: Y
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Jia
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Susan M
authors.initials: SM
authors.lastname: Pinney
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wiest
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Ann G
authors.initials: AG
authors.lastname: Schwartz
authors.forename: Adi
authors.initials: A
authors.lastname: Gazdar
authors.forename: Colette
authors.initials: C
authors.lastname: Gaba
authors.forename: Henry
authors.initials: H
authors.lastname: Rothschild
authors.forename: Diptasri
authors.initials: D
authors.lastname: Mandal
authors.forename: Elena
authors.initials: E
authors.lastname: Kupert
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
authors.forename: Avinash
authors.initials: A
authors.lastname: Viswanathan
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.forename: John
authors.initials: J
authors.lastname: Minna
authors.forename: Marshall W
authors.initials: MW
authors.lastname: Anderson
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000483:Alleles; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018773:Genes, erbB-1; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation
chemical_list: D004273:DNA, Neoplasm; D066246:ErbB Receptors