p < 10 -100
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Extracellular Domain Mutations in EGFR Occur Uniquely in Glioblastoma and Favor Ligand-Independent Formation of the Active State
Susan L. McGovern, Marta L. Rojas, Anupama Gururaj, Wah Chiu, Oliver Bogler, and John N. Weinstein
Departments of Radiation Oncology, Neurosurgery, and BiostatisticsMD Anderson Cancer Center
Department of BiochemistryBaylor College of Medicine
Houston, TX
ASTRO 2012
Cancer
COSMICExtracellular
missense mutations in
EGFR
Intracellularmissense
mutations in EGFR
Lung adenoca 0 2282
Lung SCC 0 38
Lung BAC 0 48
Ovarian 0 18Head & neck 0 19
Mesothelioma 0 9
Prostate 0 29
Thyroid 0 15
Glioblastoma 68 8
Cancer
COSMIC TCGA Validation SetExtracellular
missense mutations in
EGFR
Intracellularmissense
mutations in EGFR
Extracellular missense
mutations in EGFR
Intracellularmissense mutations
in EGFRLung adenoca 0 2282
Lung SCC 0 38
Lung BAC 0 48
Ovarian 0 18Head & neck 0 19
Mesothelioma 0 9
Prostate 0 29
Thyroid 0 15
Glioblastoma 68 8 35 1
Cancer
COSMICExtracellular
missense mutations in
EGFR
Intracellularmissense
mutations in EGFR
Lung adenoca 0 2282
Lung SCC 0 38
Lung BAC 0 48
Ovarian 0 18Head & neck 0 19
Mesothelioma 0 9
Prostate 0 29
Thyroid 0 15
p < 10-100
What is the pattern of missense mutations in EGFR in glioblastoma?
21 missense mutations (A289V/D/T)
14 missense mutations (G598V)
7 missense mutations (R108K)
4 missense mutations (T263P)
2 missense mutations (R324L, P596L, C620W/Y)
1 missense mutation (16 residues)
EGF
Structure of EGFR monomer (1NQL) Structure of EGFR dimer (3NJP)
extracellular
intracellular
III
III
IV
III
III
IV
R108KT263P
A289DA289T
EGFRvIIIEGFR
1726-zeo
Rel
ativ
e P
hosp
hory
latio
n Y1068 Serum starved
EGF
R108KT263P
A289DA289T
EGFRvIIIEGFR
1726-zeo
Rel
ativ
e P
hosp
hory
latio
n
Y845 Serum starved
EGF
Point mutants show increased phosphorylation in the absence of EGF.
Bogler lab, MDACC
Bogler lab, MDACC
Point mutations have worse survival than wt EGFR.
Point mutants have better survival than EGFR vIII.
XenograftMedian survival (d)
p-value vs. wt EGFR
p-value vs. EGFR vIII
wt EGFR 16 --- 0.0001
EGFR vIII 13 0.0001 ---
R108K 13 0.0017 0.06
T263P 17 0.068 0.0001
A289D 14 0.03 0.0005
A289T 14 0.012 0.0005
Mice transfected with xenografts expressing point mutants or EGFR vIII.
A289T: pulling open latch?A289D: pulling open latch?R108K: loss of hydrogen bondswild type EGFR
A289
R108K
E84A289D
R108
E84A289
R108
E84A289T
R108
E84A289
R108
E84
I
II
III
IV
Model for A289T/D or R108K
Adapted from Li, et al. Cancer Cell (2005)
I
III
IV
III
III
IV
II
IV
EI
IIIII
IV
E
III
III
IVI
III
IIIV
A289V or R108K
wt EGFR
95% 5%
EI
III
IV
III
III
IV
II
IV
E
IIII
IIIV
III
III
IV
Conclusions
1. In GBM, EGFR missense mutations preferentially occur in extracellular domain.
2. Many of these mutations may promote ligand-independent activation of EGFR.
3. Better understanding of the biophysical and cellular consequences of these mutations may help identify subgroups of glioblastoma patients that may benefit from EGFR inhibitors (+ other therapies?)