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Table 3 Targeted Inhibition of signalling molecules show differential effects between EGF- and hypoxia-induced EMT

From: Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines

 

Cell line:

 

PMC42-ET

PMC42-LA

MDA-MB-468

 

Stimulus:

 

EGF

HPX

 

Measured IC 50 for:

Biochemical assay (published data from compound vendors)

% vimentin-positive cells (μM)

Cell count ( μM)

% vimentin-positive cells ( μM)

Cell count ( μM)

% vimentin-positive cells ( μM)

Cell count ( μM)

% vimentin-positive cells ( μM)

Cell count ( μM)

Targets:

Compound name

         
 

Erlotinib (Tarceva)

EGFR (2 nM)

>25

15.04

0.18

16.42

0.14

16.42

5.71

>25

 

Lapatinib (GW572016)

EGFR (10.2 nM), HER2 (9.8 nM)

>25

2.46

0.57

1.65

4.32

2.99

1.96

1.44

a) HERs/EGFR

Vandetanib (Zactima)

VEGFR2 (40 nM), VEGFR3 (110 nM), EGFR (500 nM)

>25

1.84

0.57

1.57

0.50

3.77

-

-

 

Gefitinib (Iressa)

EGFR (33 nM)

>25

5.78

0.26

1.48

0.25

2.31

6.62

6.27

 

TOVOK (Afatinib)

Irreversible binder. EGFR (0.5 nM), HER2 (14 nM)

>25

1.24

0.02

0.96

0.03

0.26

2.38

1.01

 

AV-412

EGFR (43 nM), HER2 (282 nM)

>25

0.33

0.05

0.32

0.05

0.54

>25

0.06

 

U0126

MEK1 (70 nM), MEK2 (60 nM)

>25

>25

1.38

>25

0.38

8.74

4.99

>25

 

SL 327

MEK1 (180 nM), MEK2 (220 nM)

>25

16.43

1.43

>25

>25

12.56

>25

0.03

b) MEK-1/2

PD 198306

MEK (8 nM)

>25

1.36

0.34

2.50

0.46

0.97

1.7

2.94

 

AZD6244 (Selumetinib)

MEK1 (14 nM)

>25

>25

0.06

>25

1.38

13.71

>25

>25

 

CI-1040 (PD-184352)

MEK (1–1.3 nM)

>25

3.27

0.16

1.40

0.19

2.00

4.7

6.33

 

PD0325901

MEK (0.33 nM)

>25

>25

<0.02

>25

<0.02

2.77

4.17

0.06

 

PD173955-Analogue 1

c-Src (9 nM)

>25

5.94

>25

6.28

1.70

3.40

6.55

>25

 

Saracatinib (AZD0530)

Src (2.7 nM)

>25

0.75

0.94

0.50

>25

6.35

>25

0.72

c) Src family

Bosutinib (SKI-606)

Src (1.2 nM), Abl (1 nM)

>25

1.40

0.23

1.17

0.25

1.05

1.19

0.54

 

Dasatinib (BMS-354825)

Src (0.8 nM), Abl (0.6 nM)

>25

0.04

0.76

<0.02

0.64

5.59

>25

0.04

 

PD173952

Src (8 nM), Lck (5 nM), FGFR1 (100 nM)

>25

0.35

1.61

0.23

0.10

0.25

-

-

 

PIK-90

PI3K (α 11 nM, β 350 nM, γ 18 nM, δ 58 nM)

>25

16.35

>25

16.36

3.26

>25

>25

<0.02

 

ZSTK474

PI3K (α 17 nM, β 53 nM, γ 6 nM)

>25

0.83

>25

2.11

0.21

0.72

2.35

>25

 

GDC-0941

PI3K (α 3 nM, β 33 nM, γ 75 nM, δ 3 nM)

>25

0.46

8.67

1.18

1.27

1.79

4.69

4.88

 

BEZ-235 (NVP-BEZ235)

p110 (α 4 nM, β 75 nM, γ 5 nM, δ 7 nM)

>25

0.06

>25

>25

0.02

0.05

0.05

3.43

d) PI3K/mTOR

PI103

DNA-PK (2 nM), mTORC1 (20 nM), PI3K-C2b (26 nM), p110 (α 8 nM, β 88 nM, γ 150 nM, δ 48 nM)

15.18

0.32

>25

1.82

0.38

0.88

1.22

1.04

 

GNE-493

PI3K (α 3.4 nM, β 12 nM, γ 16 nM, δ 16 nM)

>25

1.11

>25

12.09

0.29

1.45

0.99

6.41

 

GSK2126458 (HYR-582)

Ki: P110 (α 0.019 nM, β 0.13 nM, γ 0.06 nM, δ 0.024 nM), mTORC1 (0.18 nM), mTORC2 (0.3 nM)

>25

0.02

6.69

0.62

<0.02

0.08

0.29

0.74

 

GNE-490

PI3K (α 3.5 nM, β 25 nM, γ 5.2 nM, δ 15 nM)

>25

2.16

>25

2.23

0.93

1.25

12.68

>25

 

LY294002

PI3K (α 0.5 uM, β 0.97 uM, γ 0.57 uM)

>25

14.86

>25

12.12

4.18

13.22

>25

>25

 

GSK690693

Akt1 (2 nM), Akt2 (13 nM), Akt3 (9 nM)

>25

>25

>25

8.32

>25

3.31

>25

>25

 

A-674563

Ki: Akt1 (11 nM), PKA (16 nM), CDK2 (46 nM), ERK2 (260 nM)

>25

0.48

0.17

0.76

0.65

0.25

2.83

0.60

 

Akt-i-1

Akt1 (4.6 μM)

>25

>25

>25

>25

>25

6.46

>25

12.30

e) Akt

Akt-i-1/2

Akt1 (58 nM), Akt2 (210 nM)

>25

>25

>25

>25

>25

2.82

>25

4.79

 

AT7867

Akt1 (32 nM), Akt2 (17 nM), Akt3 (47 nM), PKA (20 nM)

>25

2.63

>25

0.24

>25

2.95

>25

4.57

 

AZD5363

Akt1 (3 nM), Akt2 (8 nM), Akt3 (8 nM), ROCK2 (56 nM)

>25

>25

>25

>25

0.63

>25

>25

>25

 

Merck-22-6

Akt1 (138 nM), Akt2 (212 nM)

>25

4.27

>25

1.48

>25

0.46

>25

0.55

 

MK-2206

Akt1 (8 nM), Akt2 (12 nM), Akt3 (65 nM)

>25

5.62

>25

3.16

>25

1.86

>25

9.77

  1. Inhibition of vimentin expression and cell counts by a selection of kinase inhibitors. Shown are the IC50 values (where the fraction of vimentin positive cells, or the cell count, was reduced by 50% compared to the controls). Concentrations are specified in μM units.
  2. Inhibitors have been grouped according to the kinases they target. The dose–response curves for selected kinase inhibitors are shown in Figure 4. For reference, the IC50 values of each compound measured in biochemical assays with purified enzymes are included.