Drug-sensitive FGFR2 mutations in endometrial carcinoma.
Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.
Dutt
Amit
A
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Salvesen
Helga B
HB
Chen
Tzu-Hsiu
TH
Ramos
Alex H
AH
Onofrio
Robert C
RC
Hatton
Charlie
C
Nicoletti
Richard
R
Winckler
Wendy
W
Grewal
Rupinder
R
Hanna
Megan
M
Wyhs
Nicolas
N
Ziaugra
Liuda
L
Richter
Daniel J
DJ
Trovik
Jone
J
Engelsen
Ingeborg B
IB
Stefansson
Ingunn M
IM
Fennell
Tim
T
Cibulskis
Kristian
K
Zody
Michael C
MC
Akslen
Lars A
LA
Gabriel
Stacey
S
Wong
Kwok-Kin
KK
Sellers
William R
WR
Meyerson
Matthew
M
Greulich
Heidi
H
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D051497:Receptor, Fibroblast Growth Factor, Type 2