Supplementary Table Section
Table legends
Table 1: Anti-EGFR drugs that are approved for cancer treatment.
Table 2: Cells used for recombinant expression of EGFR variants. Summary of
cellular models transiently (t) or stably (s) transfected with EGFR variants.
Table 3: NSCLC cells with endogenous EGFR mutations and wildtype EGFR.
Summary of lung cancer cell lines with endogenous EGFR kinase domain mutations
and wildtype EGFR.
1
Cell lines available at ATCC.
2
Cell lines that have been
successfully transfected according to published literature.
Table 4: Summary on clinical examination conducted in the context of EGFR
kinase domain mutations in NSCLC patients. Adapted from Sequist et al. (Sequist
et al., 2005) and updated; “---“ indicates that data were not explicitly reported in the
cited articles. Some of the numbers were calculated from published primary data.
Response as defined in the cited articles.
in calculation of median survival.
3
2
1
Only Japanese patients (n=10) included
Includes silent mutations.
4
All stable disease.
5
These data comprise only a part of the total data from IDEAL and INTACT trials. 6 not
reached (NR) at time of publication.
Table 5: Prevalence of EGFR kinase domain mutations in NSCLC patients and
their correlation with other molecular events. The right column (*) depicts
selected factors that may be deregulated or mutated in lung cancer, but have not yet
been extensively analyzed in context with EGFR kinase domain mutations.
Tables
Table 1: Anti-EGFR drugs that are approved for cancer treatment.
Drug
Gefitinib
(ZD1839/ Iressa)
Company
Compound Class
Indications
Astra Zeneca
TKI
NSCLC after failure
of standard
treatments
OSI
Pharmaceuticals/
Genentech/ Roche
TKI
NSCLC after failure
of standard
treatments
ImClone Systems/
Bristol-Myers
Squibb/ Merck
KGaA
Chimeric anti-EGFR
monoclonal antibody
YM BioSciences/
Oncoscience/
CIMAB SA/ Biocon
Biopharmaceuticals
Humanized antiEGFR monoclonal
antibody
Abgenix/ Amgen
Fully human antiEGFR monoclonal
antibody
Advanced colon
rectal cancer (CRC)
and squamous cell
carcinoma of the
head and neck
(SCCHN)
SCCHN (in India,
Argentina, Columbia
and Cuba),
nasopharyngeal
cancer (in China)
Chemotherapyresistant CRC
(de Bono and Rowinsky,
2002; Laskin and
Sandler, 2004)
Erlotinib
(CP-358,774/
Tarceva/ OSI-774)
(de Bono and Rowinsky,
2002; Laskin and
Sandler, 2004)
Cetuximab
(C225/ Erbitux)
(Janmaat and Giaccone,
2003; Harding and
Burtness, 2005)
Nimotuzumab
(TheraCim/ hR-3)
(Spicer et al., 2005)
Panitumumab
(ABX-EGF/ Vectibix)
(Davis et al., 1999;
Cohenuram and Saif,
2007)
Table 2: Cells used for recombinant expression of EGFR variants.
Cell line
Tissue
Cos-7
African green monkey, kidney
NIH-3T3
Murine fibroblasts
HEK293T
Human kidney
NMuMg
CHO
Murine mammary epithelium
Chinese hamster ovary
H1299
32D
Human NSCLC
Murine IL-3 dependent myeloid
cells
Human cervix tumor
Human tracheobronchial
epithelium
Murine IL-3 dependent proB
lymphoid cells
Murine fibroblasts
Human lung large cell carcinoma
Hela
hTBE
Baf/F3
NR6
PC-13
Transient (t)/ Stable (s)
transfection
t (Lynch et al., 2004a),
t (Sordella et al., 2004),
t (Choong et al., 2006)
s (Greulich et al., 2005),
t (Greulich et al., 2005),
s (Mukohara et al., 2005),
s (Shimamura et al., 2005),
s (Alvarez et al., 2006),
s (Arao et al., 2004),
t (Pao et al., 2004),
t (Amann et al., 2005),
s (Sakai et al., 2006),
s (Sordella et al., 2004)
s (Amann et al., 2005),
t (Engelman et al., 2005)
s (Chen et al., 2006)
s (Chen et al., 2006)
t (Greulich et al., 2005)
s (Greulich et al., 2005)
s (Jiang et al., 2005)
s (Carey et al., 2006)
t (Akca et al., 2006)
Table 3: NSCLC cells with endogenous EGFR mutations and wildtype EGFR.
Cell line
EGFR
Other characteristics
L858R, EGFR amplification
high ErbB2, ErbB3 and epiregulin expression
detectable amphiregulin
no secretion of TGF
delE746-A750
lack of PTEN
wildtype K-RAS
L858R + T790M
wildtype K-RAS
delE746-A750, amplification
high ErbB3, epiregulin and amphiregulin expression
detectable ErbB2
del746-750; high expression
of EGFR
delL747-E749
detectable epiregulin and amphiregulin
low Akt expression
no ErbB2 and ErbB3
wildtype K-RAS
detectable ErbB3, epiregulin and amphiregulin
ErbB2 expression low
wildtype K-RAS
high ErbB3 expression
medium EGF and TGF expression
low ErbB2 and ErbB4 expression
high ErbB3 expression
Non-specified deletion
mutation
contradicting K-RAS mutation data (Coldren, 2006;
Okudela, 2004)
[1,2]
Wildtype
ErbB2-G776V mutation
wildtype K-RAS
[1]
Wildtype
TGF secretion
wildtype K-RAS
Wildtype
high ErbB3 expression
detectable ErbB2 and amphiregulin
no ErbB4 expression
K-RAS mutation
K-RAS mutation
H3255
(Tracy, 2004; Amann et al., 2005; Engelman et al., 2005;
Haura et al., 2005; Paez et al., 2004; Mukohara et al., 2005;
Shimamura et al., 2005; Alvarez, 2006; Engelman, 2006)
[1]
H1650
(Sordella et al., 2004; Kwak et al., 2005; Shimamura et al.,
2005; Janmaat et al., 2006; Haura et al., 2005)
[1]
H1975
(Sordella et al., 2004; Haura et al., 2005; Kwak et al., 2005;
Pao et al., 2005a; Shimamura et al., 2005; Yauch et al.,
2005; Engelman et al., 2006)
[1]
HCC-827
(Amann et al., 2005; Fujimoto, et al., 2005; Mukohara et al.,
2005; Alvarez et al., 2006, Engelmann et al., 2006)
HCC2279
(Fujimoto et al., 2005; Coldren et al., 2006)
del746-750, S752V;
medium EGFR expression
H4006
(Fujimoto et al., 2005; Coldren et al., 2006)
[2]
PC-9
(Kakiuchi et al., 2004; Ono et al., 2004; Tracy et al., 2004;
Mukohara et al., 2005; Akca et al., 2006; Sakai et al., 2006)
DFCILU-011
delE746-A750, also express
some wildtype EGFR
(Engelman et al., 2005; Mukohara et al., 2005)
[2]
H820
(Coldren et al., 2006)
H1781
(Paez et al., 2004; Yauch et al., 2005)
H1666
Paez et al., 2004; Tracy et al., 2004; Sordella et al., 2004;
Mukohara et al., 2005; Shimamura et al., 2005)
H358
[1,2]
(Kakiuchi et al., 2004; Sordella et al., 2004; Engelman et al.,
2005; Haura et al., 2005; Pao et al., 2005a)
H1734
[1,2]
Wildtype
(Sordella, 2004; Pao et al., 2005a)
[1]
Wildtype, small increase in
copy number
[1,2]
Wildtype, small increase in
copy number
H1819
(Amann et al., 2005; Fujimoto et al., 2005)
H1299
(Lee et al., 2003; Amann et al., 2005; Engelman et al.,
2005; Haura et al., 2005; Yauch et al., 2005, Akca et al.,
2006)
A549
[1,2]
Wildtype
(Tracy et al., 2004; Amann et al., 2005; Engelmann et al.,
2005; Haura et al., 2005; Mukohara et al., 2005; Shimamura
et al., 2005; Yauch et al., 2005)
H441
[1,2]
Wildtype
(Paez et al., 2004; Mukohara et al., 2005; Yauch et al.,
2005)
H23
[1,2]
Wildtype
(Engelman et al., 2005; Yauch et al., 2005)
H292
high TGF expression
low ErbB2 and ErbB3 expression
detectable PTEN
no EGF expression
K-RAS mutation
ErbB2 and ErbB3 constitutively active
detectable TGF secretion
K-RAS and p53 mutation
lack of PTEN
no ErbB2 and ErbB3 expression
p53 and K-RAS mutation
[1,2]
Wildtype, high expression
[1,2]
Wildtype
medium ErbB3 and EGF expression
detectable PTEN
low ErbB2, HB-EGF and TGF expression
K-RAS wildtype
High ErbB2 and ErbB3 expression
[1,2]
Wildtype, small increase in
copy number
No ErbB2 and ErbB3 expression
wildtype K-RAS
Wildtype
K-RAS mutation
(Janmaat et al., 2006)
Calu-3
ErbB2 amplification
high ErbB3 expression
detectable amphiregulin and epiregulin
medium TGF expression
low ErbB3 expression
no ErbB2 and ErbB4 expression
p53 mutation, wildtype PTEN and K-RAS
(Engelman et al., 2005)
Calu-1
(Amann et al., 2005; Shimamura et al., 2005; Yauch et al.,
2005)
H2030
(Pao et al., 2005a)
[1]
Table 4: Summary on clinical examination conducted in the context of EGFR
kinase domain mutations in NSCLC patients.
Authors
Lynch et al.,
2004a
Mut
Wt
Number
of
subjects
8
8
Paez et al.,
2004
Mut
5
100
---
100
60
---
Wt
4
0
---
75
75
---
Pao et al.,
2004
Mut
17
100
---
---
---
---
Wt
Mut
43
22
12
77
-----
-----
-----
-----
Wt
Mut
38
8
13
78
-----
--100
--75
--88
Wt
Mut
8
9
14
89
--25
13
89
75
56
63
78
Wt
Mut
12
33
17
83
14
NR 6
58
97
25
58
0
61
Wt
Mut
26
17
10
65
~17
31
31
82
31
71
31
65
Wt
Mut
73
17
14
94
7
NR 6
--100
--65
--82
Wt
Mut
51
4
12
100
10
---
59
100
24
50
16
75
Wt
Mut
8
8
0
88
--16 2
63
100
50
50
25
62
Wt
Mut
24
10
13
100
22
---
77
100
27
60
20
60 (n)
Wt
Mut
10 3
12
40
67
--NR 6
80
92
50
75
50 (n)
91 (n)
Wt
Mut
Wt
Mut
Wt
18
19
81
39
27
6
16
7
82
11
7
----20
7
56
----97
89
28
----46
39
39 (n)
----54
37
Mut
Wt
Mut
Wt
4
9
13
14
100
67 4
54
14
16
11
20
8
100
78
85
86
75
22
54
21
25
0
-----
Kim et al.,
2005
CortesFunes et al.,
2005
Cappuzzo et
al., 2005a
Chou et al.,
2005
Mut
Wt
Mut
6
21
10
100
--60
16
5
13
83
--100
50
--70
67
--60
Wt
72
8
5
44
25
20
Mut
Wt
Mut
Wt
15
74
33
21
53
5
52
19
21
8
15
5
80
62
88
---
53
31
55
40
9
76
Uramoto et
al., 2006
Mut
Wt
9
11
78
0
13
4
100
72
44
45
56
27
Bell et al.,
2005a
Mut
Wt
13 5
56 5
46 5
95
-----
80
51
50
29
39
14
Mu et al.,
2005
Mut
10
100
---
90
70
---
33
50
14
69
9
-----------
64
83
50
96
88
45
50
25
79
45
--67
38
79
55
Pao, 2005b
Huang et al.,
2004
Tokumo et
al., 2005
Mitsudomi et
al., 2005
Han et al.,
2005
Taron et al.,
2005
Kondo et al.,
2005
Rosell et al.,
2005
Tomizawa et
al., 2005
Zhang et al.,
2005
Tsao et al.,
2005
Takano et al.,
2005
Niho et al.,
2006
Kimura et al.,
2006
Ishikawa et
al., 2005
Shih et al.,
2006
EGFR
status
Wt
Mut
Wt
Mut
Wt
3
12
6
7
29
33
Response rate
to gefitinib or
erlotinib (%) 1
100
13
Median
survival
(months)
-----
Adenocarcinoma
or BAC (%)
Female
(%)
100
---
63
---
NeverSmokers/NonSmokers (%)
63
---
Table 5: Prevalence of EGFR kinase domain mutations in NSCLC patients and
their correlation with other molecular events.
Positive
Correlation
Negative
Correlation
No
Correlation
Unclear
Correlation (*)
Increased genomic
EGFR copy number
(Taron et al., 2005;
Takano et al., 2005)
Increased methylation
of SPARC (secreted
protein acidic and rich
in cysteine) promoter
region (Suzuki et al.,
2006)
EGFR
overexpression
(Taron et al.,
2005)
Increased number of
CA repeats (Taron et
al., 2005)
K-RAS mutation
(Kosaka et al., 2004;
Pao et al., 2005b;
Soung et al., 2005;
Shigematsu et al.,
2005a; Yokoyama et
al., 2006)
ErbB2 mutation
(Stephens et al., 2004;
Shigematsu, et al.,
2005b; Yokoyama et
al., 2006)
p53 mutation
(Kondo et al.,
2005)
Mutation of B-Raf (vraf murine sarcoma
viral oncogene
homolog B1) (Naoki
et al., 2002; Brose et
al., 2002);
Deregulation of RasRaf-MAPK signaling
(Adjei, 2005)
PI3K mutation
(Samuels et al.,
2004; Kawano et al.,
2006)
Increased phosphoSTAT5 levels (Haura
et al., 2005)
ErbB2
amplification
(Endo et al.,
2006)
Activation of mTOR
(mammalian target of
Rapamycin)
signaling (Conde et
al., 2006)
ErbB4 mutation
(Soung et al.,
2006)
ErbB2 and
concomitant EGFR
gene amplification
(Cappuzzo et al.,
2005b)
EGFR
overexpression
(Suzuki et al., 2005)
Increased
phospho-Akt
levels (Han et al.,
2006)
Increased
phospho-MAPK
levels (Han et al.,
2006)
Calveolin-1
mRNA
overexpression
(Taron et al.,
2005)
c-Met (hepatocyte
growth factor
receptor) mutation
(Kong-Beltran et al.,
2006)
Deregulation of Wnt
(wingless-type MMTV
integration site
family) signaling
(Uematsu et al.,
2003)
PP2a (protein
phosphatase 2A)
(Wang et al., 1998)
Neurotrophin/
neurotrophin receptor
expression (Ricci et
al., 2001)
EMP-1 (epithelial
membrane protein 1)
expression (Jain et
al., 2005)
SOCS-3 (suppressor
of cytokine signaling
3) expression (He et
al., 2003)
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