Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.
BACKGROUND
Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.


RESULTS
Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.


CONCLUSIONS
Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
Lee
Jeffrey C
JC
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts, United States of America.
Vivanco
Igor
I
Beroukhim
Rameen
R
Huang
Julie H Y
JH
Feng
Whei L
WL
DeBiasi
Ralph M
RM
Yoshimoto
Koji
K
King
Jennifer C
JC
Nghiemphu
Phioanh
P
Yuza
Yuki
Y
Xu
Qing
Q
Greulich
Heidi
H
Thomas
Roman K
RK
Paez
J Guillermo
JG
Peck
Timothy C
TC
Linhart
David J
DJ
Glatt
Karen A
KA
Getz
Gad
G
Onofrio
Robert
R
Ziaugra
Liuda
L
Levine
Ross L
RL
Gabriel
Stacey
S
Kawaguchi
Tomohiro
T
O'Neill
Keith
K
Khan
Haumith
H
Liau
Linda M
LM
Nelson
Stanley F
SF
Rao
P Nagesh
PN
Mischel
Paul
P
Pieper
Russell O
RO
Cloughesy
Tim
T
Leahy
Daniel J
DJ
Sellers
William R
WR
Sawyers
Charles L
CL
Meyerson
Matthew
M
Mellinghoff
Ingo K
IK
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors