178014 2 merged 1494965256 · 6/1/2017 · (slwkholdo ryduldq fdqfhu (2& uhsuhvhqwv wkh prvw olih...
Transcript of 178014 2 merged 1494965256 · 6/1/2017 · (slwkholdo ryduldq fdqfhu (2& uhsuhvhqwv wkh prvw olih...
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×
× ×
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Figure 1.
A
B
D
C EDMSO JQ1 THZ1
JQ1 (μM)
0 0.1 0.3 1 3 0 0.03 0.1 0.3 1
THZ1 (μM)
CO
V 4
13
BO
VC
A420
SK
OV
3
THZ1
THZ1
THZ1
COV 413B
0 0.05 0.1 0.5 1
RNAPII S2
CDK7
Tubulin
RNAPII S5
RNAPII S7
RNAPII S2
CDK7
Tubulin
RNAPII S5
RNAPII S7
RNAPII S2
CDK7
Tubulin
RNAPII S5
RNAPII S7
SKOV3
0 0.05 0.1 0.5 1
OVCA420
0 0.05 0.1 0.5 1
THZ1
Dinaciclib
Flavopiridol
Romidepsin
Panobinostat
PF−04929113
AT13387
Torin 2
INK 128
BEZ235
BI 6727
BI 2536
MLN2238
Bortezomib
Dasatinib
YM155
Pemetrexed
Abitrexate
Gemcitabine
Raltitrexed
Paclitaxel
Docetaxel
Topotecan
Doxorubicin
Epirubicin
CDK
INHIBITOR PubChemID TARGET COV 413B OVCA420 SKOV3
CDK
CDK
HDAC
HDAC
HSP
HSP
mTOR
mTOR
mTOR
PLK
PLK
Proteasome
Proteasome
Src
IAP
chemo
chemo
chemo
chemo
chemo
chemo
chemo
chemo
chemo
73602827
46926350
5459219
5352062
6918837
44195571
11955716
51358113
45375953
11977753
10461508
11364421
25183872
387447
3062316
46931000
394493
126941
60750
104758
36314
148124
60700
31703
41867
High
IC50 < 0.5μM
96-well plate
Imaging using ArrayScan Infinity
Ovarian cancer cells
Inhibitor library
inhib
itor a
ctiv
ity
Low
CO
V 4
13
BO
VC
A4
20
SK
OV
3
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-17-0078
Figure 2.
A
C D
E F
B
Pol II S2
cleaved PARP
CDK7
Tubulin
Pol II S5
Pol II
Pol II S7
4 8 12 16 200
300
600
900
1200
1500
1800
Vehicle
HEY xenograftA2780 xenograft
Time (days) Time (days)
THZ1
**
*
*
*
**
* **
n=10 n=10
3 6 9 12 15 18 21 24 270
200
400
600
800
1000
1200
Vehicle
THZ1
Tu
mo
r vo
lum
e (
mm
3)
A2780 COV 413B OVCA420
0 0.05 0.1 0.5 1 0 0.05 0.1 0.5 1 0 0.05 0.1 0.5 1 THZ1 (μM)
THZ1 concentration (μM)
0.010.001 0.1 1
inhibitor concentration (μM)
0.010.001 0.1 1 10
0
20
40
60
80
120
100
Ce
ll via
bili
ty (
%)
0
20
40
60
80
120
100
Ce
ll via
bili
ty (
%)
COV 362
A2780
TOV-112D
COV 413B
DOV 13
OV90
SW982
OVCA433
PA1
OVCAR5
HEY
IGROV1
SKOV3
OVCA420
OVTOKO
OVCAR8
COV 318
ES-2
SW
98
2
DMSO THZ1
OV
CA
433
PA
1O
VC
AR
5H
EY
IGR
OV
1
SK
OV
3
DMSO THZ1
OV
CA
420
OV
TO
KO
OV
CA
R8
CO
V 3
18
ES
-2
CO
V 3
62
DMSO THZ1
A2
78
0T
OV
-11
2D
CO
V 4
13
BD
OV
13
OV
90
A2
78
0C
OV
36
2E
S-2
JQ1 (μM)
0 0.1 0.3 1 103 0 0.030.01 0.1 0.3 1
THZ1 (μM)
A2780+JQ1A2780+THZ1COV 362+JQ1COV 362+THZ1ES-2+JQ1ES-2+THZ1
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-17-0078
Figure 3.
A
C
D E
B
Pol II S2
CDK7CDK7
OVCA420
H3
CDK7
H3
SW98
2
HEY
A278
0
DO
V 13
OVT
OKO
CO
V 31
8
SKO
V3
OVC
A420
MC
AS
TOV-
112D
PA1
IGR
OV1
OVC
AR5
OVC
A433
OVC
AR8
CO
V 41
3B
ES-2
OV9
0
sgEG
FP
sgC
DK7
-1
sgC
DK7
-2
sgC
DK7
-3
Pol II S5
Pol II S7
CDK4
CDK6
CDK9
Actin
positivenegative
A2780
sgEGFP sgCDK7-1 sgCDK7-2 sgCDK7-3 sgEGFP sgCDK7-1 sgCDK7-2 sgCDK7-3
COV 413B
HEY
ES-2
SKOV3
OVCA420
sgEGFP
sgCDK7-1
sgCDK7-2
sgEGFP
sgCDK7-1
sgCDK7-2
ES-2
HEY
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Follow up (months)
Epithelial OvCa
Ove
rall
Surv
ival
(pro
b.)
P=0.036
n=28
n=22
CDK7 negativeCDK7 positive
sgEGFP
sgCDK7-1
sgCDK7-2
sgEGFP
sgCDK7-1
sgCDK7-2
0.00
0.05
0.10
0.15
0.20
0.25
0.30 *
Tum
or w
eigh
t (g)
Tum
or w
eigh
t (g)
0.00
0.05
0.10
0.15
0.20
0.25 *
A2780
sgEG
FP
sgC
DK7
-1
sgC
DK7
-2
sgC
DK7
-3
COV 413B
sgEG
FP
sgC
DK7
-1
sgC
DK7
-2
sgC
DK7
-3
ES-2
sgEG
FP
sgC
DK7
-1
sgC
DK7
-2
sgC
DK7
-3
HEY
sgEG
FP
sgC
DK7
-1
sgC
DK7
-2
sgC
DK7
-3
SKOV3
sgEG
FP
sgC
DK7
-1
sgC
DK7
-2
sgC
DK7
-3
0.0
0.5
1.0
* * *
* * *
* * *
* * *
* * *
* * *
rela
tive
prol
ifera
tion
0.0
0.5
1.0
rela
tive
prol
ifera
tion
0.0
0.5
1.0
rela
tive
prol
ifera
tion
0.0
0.5
1.0
rela
tive
prol
ifera
tion
0.0
0.5
1.0
rela
tive
prol
ifera
tion
0.0
0.5
1.0re
lativ
e pr
olife
ratio
n
sgEGFP
sgCDK7-1
sgCDK7-2
sgCDK7-3
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Figure 4.
A B
THZ1 (nM)
All
11
014 a
ctive tra
nscripts
(F
PK
M>
1)
COV 413B
Gene Expression
Log2 Fold Change
0
0-4 4
100
All
10949 a
ctive tra
nscripts
(F
PK
M>
1)
Gene Expression
Log2 Fold Change
OVCA420
0-4 4
0 100
All
9753 a
ctive tra
nscripts
(F
PK
M>
1)
Gene Expression
Log2 Fold Change
SKOV3
0-4 4
0 100
0 5 10 15 20 25 30 35 40 45
Spliceosome
Homologous recombination
Cell cycle
RNA transport
Fanconi anemia pathway
double-stranded DNA binding
poly(A) RNA binding
protein binding
centrosome
mitochondrion
nucleolus
nucleus
nucleoplasm
transcription, DNA-templated
double-strand break repair via synthesis-dependent strand annealing
organelle organization
tRNA processing
mitotic nuclear division
DNA replication
double-strand break repair via homologous recombination
gene expression
double-strand break repair
mitotic cell cycle
DNA repair
cell division
biological process
cellular component
molecular function
KEGG pathway
-Log10 FDR
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-17-0078
Figure 5.
A
B
C
COV 413B
LAMA5 (4)
ZMIZ1 (6)
ITGB6 (9)
TRIO (39)
SOX4 (125)
EGFR (226)
PAX8 (287)
KLF13 (301)
PAX2 (348)
FGF18 (349)
MYC (439)
HES1 (483)
CDK5 (750)
E2F3 (862)
KLF9 (528)
0.0
0 5000 10000
Ranked Enhancers Ranked Enhancers Ranked Enhancers
15000 20000 0 5000 10000 15000 0 5000 10000 15000 20000
1.0
2.0
3.0
0.0
0.5
1.0
1.5
0.0
0.5
1.0
1.5
OVCA420 SKOV3
H3
K2
7A
c s
ign
al (X
10
5)
97
9 s
up
er-
en
ha
nce
rs
75
2 s
up
er-
en
ha
nce
rs
23
7 s
up
er-
en
ha
nce
rs
COV 413B OVCA420 SKOV3
THZ1 versus DMSOTHZ1 versus DMSO THZ1 versus DMSO
En
rich
me
nt
sco
re
-0.10
-0.15
-0.20
-0.05
0.00
0.05
0.10
En
rich
me
nt
sco
re
-0.20
-0.15
-0.10
-0.25
-0.30
-0.05
0.00
0.05
En
rich
me
nt
sco
re
-0.10
-0.15
-0.20
-0.25
-0.05
0.00
0.05
FDR=0 FDR=0 FDR=0
COV 413B
OVCA420
SKOV3
−1
0
1
2
3
−1
0
1
2
3
−1
0
1
2
3
0 50 100 150 200 250 kb
ZMIZ1
rpm
/bin
0 50 100 150 200 kb
ITGB6
COV 413B
OVCA420
SKOV3
0
2
4
0
2
4
0
2
4
rpm
/bin
7550250 kb
PAX8
COV413B
OVCA420
SKOV3
−1
0
1
2
3
−1
0
1
2
3
−1
0
1
2
3
rpm
/bin
SRC (14)
LAMA5 (34)
ITGB6 (54)
BCL2L1 (65)
FGFR3 (89)
ID2 (225)
ZMIZ1 (233)
IGF1R(297)
FOSL2 (331)
SMAD3 (440)
TGFA (466)
CCND1 (497)
JUN (659)
HES1 (569)
TRIO (488)
HOXB5 (2)
ITGB6 (16)
BCL2L1 (50)
CENPA (37)
EHF (79)
SLC2A1 (60)
JUNB (87)
IGFBP4 (103)
FZD2 (112)
ZMIZ1 (154)
HNF1B (156)
SREBF1 (166)
PDGFC (209)
PAX8 (242)
LIF (199)
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Figure 6.
A
B D
C
ELK3FOSL2FOSL1MYC
MYC FOSL1 FOSL2 ELK3 MYC FOSL1 FOSL2 ELK3 MYC FOSL1 FOSL2 ELK3
sgEGFP
CO
V 4
13
BO
VC
A4
20
SK
OV
3
sgMYC-1 sgMYC-2 sgFOSL1-1 sgFOSL1-2 sgFOSL2-1 sgFOSL2-2 sgELK3-1 sgELK3-2
0.0
0
50
100
0
50
100
0
50
100
0.5
1.0
0.0
0.5
1.0
0.0 sgE
GF
P
sg
MY
C-1
sg
MY
C-2
sgF
OS
L1-1
sgF
OS
L1-2
sgF
OS
L2-1
sgF
OS
L2-2
sg
EL
K3
-1
sg
EL
K3
-2
0.5
1.0
COV 413B
OVCA420
SKOV3
−1
0
1
2
−1
0
1
2
−1
0
1
2
0 25 50 75
COV 413B
OVCA420
SKOV3
−1
0
1
2
3
−1
0
1
2
3
−1
0
1
2
3
0 10 20 30
COV 413B
OVCA420
SKOV3
0
2
4
0
2
4
0
2
4
0 10 20 30
COV 413B
OVCA420
SKOV3
−1
0
1
2
3
4
−1
0
1
2
3
4
−1
0
1
2
3
4
0 5 10 15 kb kb kb kb
rpm
/bin
COV413B
**
*
*
*
*
*
*
**
*
*
**
* ** * * *
* *
* *
* *
* *
* *
* ** *
* *
rela
tive
pro
life
ratio
n
rela
tive
gene e
xpre
ssio
n (%
)
OVCA420
rela
tive
pro
life
ratio
n
SKOV3
rela
tive
pro
life
ratio
n
COV413B OVCA420 SKOV3
DMSOTHZ1
on Septem
ber 21, 2020. © 2017 A
merican A
ssociation for Cancer R
esearch. m
ct.aacrjournals.org D
ownloaded from
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anuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author M
anuscript Published O
nlineFirst on June 1, 2017; D
OI: 10.1158/1535-7163.M
CT
-17-0078
Published OnlineFirst June 1, 2017.Mol Cancer Ther Zhenfeng Zhang, Huixin Peng, Xiaojie Wang, et al. CDK7-dependent transcriptional addiction in ovarian cancerPreclinical efficacy and molecular mechanism of targeting
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on September 21, 2020. © 2017 American Association for Cancer Research. mct.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 1, 2017; DOI: 10.1158/1535-7163.MCT-17-0078