Therapeutic window for Wnt-driven cancers: Role of Porcupine inhibitor




Wnt signaling plays a critical role in carcinogenesis; many studies over the last two decades have identified numerous signaling components that have helped to build a molecular framework for the many branches of the Wnt signal transduction pathway. However, the diverse function, integration and specificity of the Wnt signaling are still unclear. The success of Wnt pathway inhibitors has been limited for long-time by the narrow therapeutic window afforded by the requirement for Wnt signaling in normal tissue homeostasis and the lack of predictive biomarkers of response. Porcupine is a membrane bound O-acyltransferase enzyme that is required for and dedicated to palmitoylating Wnt ligands, a necessary step in the process of Wnt ligand secretion. Inhibition of Porcupine blocks Wnt dependent activities, including LRP6 phosphorylation and the expression of Wnt target genes, such as Axin2, which in turn reduces the growth of cancer cells dependent on autocrine or paracrine Wnt signaling. LGK974 is a highly potent, selective and orally bioavailable Porcupine inhibitor and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1, a human head and neck squamous cell carcinoma model (HN30) and RNF43-mutant pancreatic xenograft models. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of Porcupine in inhibition of Wnt activity.

Key words:  Wnt signaling; Porcupine inhibitor; Carcinogenesis; LGK974

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

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  1. Anastas JN, Moon RT. Wnt signalling pathways as therapeutic targets in cancer. Nature Reviews Cancer. 2013;13:11–26.
  2. Bänziger C, Soldini D, Schütt C, Zipperlen P, Hausmann G, Basler K. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 2006;125:509–522.
  3. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr. Nature 2007;449:1003–1007.
  4. Bartscherer K, Pelte N, Ingelfinger D, Boutros M. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell 2006;125:523–533.
  5. Bilic J, Huang Y‐L, Davidson G, et al. Wnt induces LRP6 signalosomes and promotes dishevelled‐ dependent LRP6 phosphorylation. Science 2007;316:1619–1622.
  6. Caldwell GM, Jones C, Gensberg K, et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res 2004;64:883–888.
  7. Cantu C, Valenta T, Hausmann G, Vilain N, Aguet M, Basler K. The Pygo2‐H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling‐dependent transcription. Development 2013;140:2377–2386.
  8. Horst D, et al. Differential WNT activity in colorectal cancer confers limited tumorigenic potential and is regulated by MAPK signaling. Cancer Res 2012;72:1547–1556.
  9. Koo BK. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012;488:665–669.
  10. He BM, et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene 2005;24:3054–3058.
  11. Goentoro L, Kirschner MW. Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling. Mol. Cell 2009;36:872–884.
  12. Phelps RA. et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 2009;137:623–634.
  13. Yousif NG, Al-amrana FG, Hadi N, Lee J, Adrienn J. Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer. Cytokine 2013;61:223-227.
  14. Malanchi I, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature. 2008;452(7187):650–653.
  15. Heidel FH, et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell 2012;10(4):412–424.
  16. Nusse R. Wnts and Hedgehogs: Lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development 2003;130(22):5297–5305.
  17. Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333(6046):1157–1160.
  18. Proweller A, et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 2006;66(15):7438–7444.
  19. Nicolas M, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33(3):416–421.
  20. Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev 2005;19(12):1485–1495.
  21. Jun Liu, Shifeng Pan, Mindy H. Hsieh. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013;110(50): 20224–20229.
  22. Alhasani S. Critical role of IL-23 signaling in prostatic cancer. American Journal of BioMedicine 2013;1(1):4-6.
  23. Gurney A, 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):11717–11722.
  24. Agrawal N, et al. Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov. 2012;2(10):899–905.
  25. Unger S, et al. Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations. Nat Genet 2008;40(3):287–289.
  26. Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. cardiovascular disorders 2011;11(1):62.
  27. Yousif NG. Fibronectin promotes migration and invasion of ovarian cancer cells through up‐regulation of FAK–PI 3 K/A kt pathway. Cell biology international 2014;38(1):85-91.
  28. Crawford HC, Fingleton BM, Rudolph-Owen LA, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene 1999;18(18):2883-2891.
  29. Spears E, Neufeld KL. Novel double-negative feedback loop between adenomatous polyposis coli and Musashi1 in colon epithelia. J. Biol. Chem 2011;286(7):4946-4950.
  30. Yang AD, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin. Cancer Res 2006;12(14 Pt 1)4147-4153.

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Research Article
DOI: 56–66
American Journal of BioMedicine Volume 2, Issue 2, pages 78-86
Received 15 January 2014; accepted 13, March 2014, Published May 14, 2014

How to cite this article
Harris AJ, Beutler EA, Liu X, Dale DA. Therapeutic window for Wnt-driven cancers: Role of Porcupine inhibitor. American Journal of BioMedicine 2014;2(2):78-86.

Case report outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

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