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Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo

Abstract

The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.

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Figure 1: PD 184352 specifically blocks activation of MAPK in whole cells.
Figure 2: Inhibition of MAPK activation by PD 184352 prevents cell cycle progression and induces a G1 block.
Figure 3: PD 184352 abrogates the transformed phenotype of colon 26 cells.
Figure 4: In vivo treatment with PD 184352 results in complete suppression of MAPK phosphorylation in tumors.
Figure 5: Oral dosing of PD 184352 impairs the growth of mouse and human colon tumors but not of P388 leukemia.
Figure 6: Excised colon tumors express high levels of pMAPK.
Figure 7: Inhibition of the MEK/MAPK pathway results in inhibition of scattering and loss of invasiveness.

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Acknowledgements

We thank J. Fergus for technical assistance.

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Sebolt-Leopold, J., Dudley, D., Herrera, R. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5, 810–816 (1999). https://doi.org/10.1038/10533

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