Transcript open "010028_McGovern_ASTRO_2012_talk"

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 Biostatistics
MD Anderson Cancer Center
Department of Biochemistry
Baylor College of Medicine
Houston, TX
ASTRO 2012
COSMIC
Cancer
TCGA Validation Set
Extracellular Intracellular Extracellular Intracellular
missense
missense
missense
missense
mutations in mutations in mutations in mutations
What
EGFR
EGFR
EGFRis the pattern
in EGFR
Lung adenoca
0
2282
Lung SCC
0
38
Lung BAC
0
48
Ovarian
0
18
Head & neck
0
19
Mesothelioma
0
9
Prostate
0
29
Thyroid
0
15
Glioblastoma
68
8
of missense
mutations in EGFR
in glioblastoma?
-100
35
p < 10
1
Structure of EGFR monomer (1NQL)
Structure of EGFR dimer (3NJP)
21 missense mutations (A289V/D/T)
14 missense mutations (G598V)
7 missense mutations (R108K)
II
I
4 missense mutations (T263P)
2 missense mutations (R324L, P596L, C620W/Y)
1 missense mutation (16 residues)
III
IV
III
EGF
II
I
IV
extracellular
intracellular
Y845
Serum starved
EGF
Relative Phosphorylation
Relative Phosphorylation
Y1068
Serum starved
EGF
Point mutants show increased phosphorylation in the
absence of EGF.
Bogler lab, MDACC
Mice transfected with
xenografts expressing
point mutants or EGFR
vIII.
Xenograft
Median
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
Point mutations have
worse survival than wt
EGFR.
Point mutants have
better survival than
EGFR vIII.
Bogler lab, MDACC
III
R108
R108K
IV
A289D
A289T
A289
I
II
A289T:
A289D:
R108K:
wild
typepulling
loss
pulling
EGFR
of hydrogen
open
open latch?
latch?
bonds
E84
Model for A289T/D or R108K
wt EGFR
E
I
I
II
III
II
I
II
E
II
E
III
I
II
III
E
III
I
IV
IV
95%
IV
IV
IV
IV
5%
A289V or R108K
I
I
II
II
IV
II
III
III
II
I
III
I
IV
IV
IV
IV
Adapted from Li, et al. Cancer Cell (2005)
Conclusions
1. In GBM, EGFR missense mutations
preferentially occur in extracellular domain.
1. Many of these mutations may promote
ligand-independent activation of EGFR.
2. 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?)