EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity.
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.
Vikis
Haris
H
Washington University, St. Louis, Missouri, USA.
Sato
Mitsuo
M
James
Michael
M
Wang
Daolong
D
Wang
Yian
Y
Wang
Min
M
Jia
Dongmei
D
Liu
Yan
Y
Bailey-Wilson
Joan E
JE
Amos
Christopher I
CI
Pinney
Susan M
SM
Petersen
Gloria M
GM
de Andrade
Mariza
M
Yang
Ping
P
Wiest
Jonathan S
JS
Fain
Pamela R
PR
Schwartz
Ann G
AG
Gazdar
Adi
A
Gaba
Colette
C
Rothschild
Henry
H
Mandal
Diptasri
D
Kupert
Elena
E
Seminara
Daniela
D
Viswanathan
Avinash
A
Govindan
Ramaswamy
R
Minna
John
J
Anderson
Marshall W
MW
You
Ming
M
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
D004273:DNA, Neoplasm; D066246:ErbB Receptors