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.
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Amit
A
Dutt
Helga B
HB
Salvesen
Tzu-Hsiu
TH
Chen
Alex H
AH
Ramos
Robert C
RC
Onofrio
Charlie
C
Hatton
Richard
R
Nicoletti
Wendy
W
Winckler
Rupinder
R
Grewal
Megan
M
Hanna
Nicolas
N
Wyhs
Liuda
L
Ziaugra
Daniel J
DJ
Richter
Jone
J
Trovik
Ingeborg B
IB
Engelsen
Ingunn M
IM
Stefansson
Tim
T
Fennell
Kristian
K
Cibulskis
Michael C
MC
Zody
Lars A
LA
Akslen
Stacey
S
Gabriel
Kwok-Kin
KK
Wong
William R
WR
Sellers
Matthew
M
Meyerson
Heidi
H
Greulich
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