The Wnt signaling pathway: prospects for pharmacological regulation
https://doi.org/10.17650/2313-805X.2016.3.1.28-31
Abstract
Wnt cascade is one of the most important signal pathways in the cell, which is required for normal embryonic development, differentiation, maintenance of stem cell phenotype and migration. Mutations in this pathway are associated with tumor growth (especially with colon cancers, hepatocarcinomas and leukemias), where they participate in maintenance of tumor-initiating cells and metastasing. Because of that there is a considerable interest to develop inhibitors of Wnt pathway as anti-tumor agent. But this inhibitors are still only in early stages of clinical investigations. In this article we review the main targets for this anti-cancer agents and their preclinical and clinical status.
About the Author
V. V. Tatarskiy
Research Institute of Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Ministry of Health of Russia
Russian Federation
Build. 15, 24 Kashirskoe Shosse, Moscow, 115478
Russian Federation
Build. 15, 24 Kashirskoe Shosse, Moscow, 115478
References
1. MacDonald B.T., He X. Frizzled and LRP5/6 receptors for Wnt/-сatenin signaling. Cold Spring Harb Perspect Biol 2012;4(12):a007880.
2. Willert K., Brown J.D., Danenberg E. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003;423(6938):448–52.
3. Takada R., Satomi Y., Kurata T. et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell 2006;11(6):791–801.
4. He T.C., Sparks A.B., Rago C. et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281(5382):1509–12.
5. Tetsu O., McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999;398(6726):422–6.
6. Ashida K., Terada T., Kitamura Y. et al. Expression of E-cadherin, alpha-catenin, beta-catenin, and CD44 (standard and variant isoforms) in human cholangiocarcinoma: an immunohistochemical study. Hepatology 1998;27(4):974–82.
7. Hu Y., Li S. Survival regulation of leukemia stem cells. Cell Mol Life Sci 2016;73(5):1039–50.
8. Moumen M., Chiche A., Decraene C. et al. Myc is required for β-catenin-mediated mammary stem cell amplification and tumorigenesis. Mol Cancer 2013;12(1):132.
9. Anastas J.N., Moon R.T. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 2013;13(1):11–26.
10. Liu J., Pan S., Hsieh M.H. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA 2013;110(50):20224–9.
11. Madan B., Ke Z., Harmston N. et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene 2015.
12. Gurney A., Axelrod F., Bond C.J. et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA 2012;109(29):11717–22.
13. Le P.N., McDermott J. D., Jimeno A. Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther 2015;146:1–11.
14. Smith D.C., Gordon M., Messersmith W. et al. A first-in-human Phase 1 study of anticancer stem cel l (CSC) agent OMP-54F28 (FZD8-Fc) targeting the WNT pathway in patients with advanced solid tumors. Mol Cancer Ther 2013;12(11 Suppl):B79.
15. Shan J., Shi D.-L., Wang J. et al. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 2005;44(47):15495–503.
16. Grandy D., Shan J., Zhang X. et al. Discovery and сharacterization of a small molecule inhibitor of the PDZ domain of dishevelled. J Biol Chem 2009;284(24):16256–63.
17. Huang S.M., Mishina Y.M., Liu S., et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009;461(7264):614–20.
18. Waaler J., Machon O., Tumova L. et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res 2012;72(11):2822–32.
19. Zhong Y., Katavolos P., Nguyen T. et al. Tankyrase inhibition causes reversible intestinal toxicity in mice with a therapeutic index < 1. Toxicol Pathol 2015;44(2):267–78.
20. Thorne C.A., Hanson A.J., Schneider J. et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Biol 2010;6(11):829–36.
21. Li L.N., Zhang H.D., Yuan S.J. et al. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 2007;121(6):1360–5.
22. Li K., Hu C., Mei C. et al. Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. J Transl Med 2014;12:167.
23. Emami K.H., Nguyen C., Ma H. et al. A small molecule inhibitor of beta-catenin/ CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 2004;101(34):12682–7.
24. Lenz H.J., Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci 2014;105(9):1087–92.
25. El-Khoueiry A.B. A phase I first-inhuman study of PRI-724 in patients(pts) with advanced solid tumors. In J Clin Oncol 2013.
26. Rosenbluh J., Nijhawan D., Cox A.G. et al. β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 2012;151(7): 1457–73.
27. Säfholm A., Tuomela J., Rosenkvist J. et al. The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin Cancer Res 2008;14(20):6556–63.
Review
For citations:
Tatarskiy V.V. The Wnt signaling pathway: prospects for pharmacological regulation. Advances in Molecular Oncology. 2016;3(1):28-31. (In Russ.) https://doi.org/10.17650/2313-805X.2016.3.1.28-31
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