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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.