npv-bez235pki-587 gdc-0980pd0325901 supplemental figure s1 structures of inhibitors nvp-bez235;...
TRANSCRIPT
NPV-BEZ235 PKI-587
GDC-0980 PD0325901
Supplemental Figure S1
Structures of Inhibitors NVP-BEZ235; PKI-587; GDC-0980 and PD0325901
pAKT Ser473
S6
-
ERK
AKT
- 0 .005 .01 .05 .1 .5 1
pAKT Thr308
Neurotensin + Insulin
pS6 Ser240/244
pERKT202/Y204
NPV-BEZ235 μM
Neurotensin + Insulin-
pAKT Ser473
S6
ERK
AKT
- 0 .005 .01 .05 .1 .5 1
pAKT Thr308
pS6 Ser240/244
pERKT202/Y204
Supplemental Figure S2
BA
NPV-BEZ235 μM
NPV-BEZ235 induces over-activation of ERK phosphorylation in MiaPaCa-2 (A) and PANC-1 (B) cells
NPV-BEZ235, µM - - 0.01 0.1 1 - - 0.01 0.1 1
PD 0325901 - - - - - + + + + +
Neurotensin+ Insulin
ERK
pERKT202/Y204
NPV-BEZ235
PD0325901, µM
- + + + + + - + + + + +
Neurotensin+ Insulin
Supplemental Figure S3
ERK
pERKT202/Y204
- - .005 .01 .05 .1 - - .005 .01 .05 0.1
A
B
The MEK inhibitor PD 0325901 suppresses ERK over-activation induced by NPV-BEZ235 at nanomolar concentrations.
Supplemental Figure S4
BA
pMEKSer217/221
MEK
Neurotensin+ Insulin Neurotensin+ Insulin
1 - - .01 .1 1 1 - - .01 .1 1
- 1 5
NPV-BEZ 235, M
PD , M1 - 1 5 1
C D
pMEKSer217/221
MEK
Serum Serum
1 - - .01 .1 1 1 - - .01 .1 1
- 1 5
NPV-BEZ 235, M
PD , M1 - 1 5 1
Overactivation of MEK phosphorylation by combination of dual PI3K/mTOR kinase inhibitor NPV-BEZ235 and MEK inhibitor PD0325901.
B
Supplemental Figure S5
PKI GDC--
Neurotensin + Insulin
0 15 30 60
-
BEZ
Time, min
Neurotensin + InsulinA
Dual PI3K/mTOR kinase inhibitors NVP-BEZ235, PKI-587 and GDC-0980 suppress PIP3 accumulation in PDAC cells in different times of stimulation.
IGF
- +
OSI-906
EGF
Lapatinib
- +
EGF
AG-1478
- +
0
1
2
3
4
0.0
0.4
0.8
1.2
1.6
0.0
0.5
1.0
1.5
2.0
AG - + Lp - + OSI - +
Fo
ld i
nc
rea
se b
y B
EZ
Fo
ld i
nc
rea
se b
y B
EZ
A
DB C
Fo
ld i
nc
rea
se b
y B
EZ
Supplemental Figure S6
NPV-BEZ235 enhances ERK pathway activation through a pathway that does not require EGFR, HER2 or insulin/IGF-1 receptor