The Canonical Wnt/β-catenin Pathway as a Therapeutic Target in Multiple Myeloma
Main Article Content
Abstract
It has been more than 30 years since Nusse and Varmus identified a new mouse proto-oncogene int1 (integration 1), conserved across multiple species, and already recognised in Drosophila as Wingless (Wg). Wnts are now known to activate multiple signalling pathways, the best understood and extensively investigated being the canonical/β-catenin dependent pathway. β-catenin signalling has been found dysregulated to varying degrees and via multiple mechanisms in both solid and haematologic cancers, including multiple myeloma (MM). Recently developed inhibitors of the Wnt canonical pathway have proven to be potentially effective against MM, with minimal side effects. There is cautious optimism that some of these inhibitors will be added in our armamentarium against MM in the not so distant future. In this review, we discuss the possible mechanisms of Wnt-canonical pathway dysregulation in the pathogenesis of MM. Furthermore, we summarise the pathway inhibitors that have been validated in the disease in pre-clinical models or clinical trials and their potential challenges.
Article Details
How to Cite
SAVVIDOU, Ioanna et al.
The Canonical Wnt/β-catenin Pathway as a Therapeutic Target in Multiple Myeloma.
Medical Research Archives, [S.l.], v. 6, n. 7, july 2018.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1821>. Date accessed: 04 dec. 2024.
doi: https://doi.org/10.18103/mra.v6i7.1821.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Pandey MK, Amin SG, Zangari M, Talamo G. Drug resistance in multiple myeloma: how to cross the border. Annals of Hematology & Oncology 2015; 2 (2):id1025.
4. Luis TC, Ichii M, Brugman MH, Kin-cade P, Staal FJT. Wnt signalling strength regulates normal hematopoi-esis and its deregulation is involved in leukaemia development. Leukemia 2012; 26 (3):414-21.
5. Anastas JN, Moon RT. WNT signal-ling pathways as therapeutic targets in cancer. Nature Reviews Cancer 2013; 13: 11-26.
6. Mikesch J-H, Steffen B, Berdel WE, Serve H, Müller-Tidow C. The emerg-ing role of Wnt signaling in the patho-genesis of acute myeloid leukemia. Leukemia 2007; 21: 1638–1647.
7. Coluccia AML, Vacca A, Dunach M, Mologni L, Redaelli S, Bustos VH et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J 2007; 26(5): 1456–1466.
8. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al. Activa-tion of the Wnt signaling pathway in chronic lymphocytic leukemia. PNAS 2004; 101 (9): 3118–3123.
9. Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH et al. Illegitimate WNT signaling pro-motes proliferation of multiple mye-loma cells. PNAS 2004;101(16): 6122-7.
10. MacDonald BT, Tamai K, Xi He. Wnt /β-catenin signalling: components, mechanisms, and diseases. Develop-mental Cell 2009; 7: 9-26.
11. Katoh M, Katoh M. Wnt signalling pathway and stem cell signalling net-work. Clin Cancer Res 2007; 13 (14): 4042-45.
12. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. Wnt and β-catenin signal-ling: diseases and therapies. Nature Reviews. 2004; 5: 689-699.
13. Staal FJT, Fodde R. Wnt signalling in adult stem-cells:tissue homeostasis and regeneration. Wnt signalling in development and disease: molecular mechanisms and biological functions. 2014; Chapter 25:329-37.
14. Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M. Canonical Wnt signalling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell 2011; 9 (4):345-56.
15. Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Pathogenesis of bone disease in multi-ple myeloma: from bench to bedside. Blood cancer Journal. 2018; 8:7.
16. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107(4):513-523.
17. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11-19.
18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513-1521.
19. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapou-los SE, Löwik CW et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005; 19(13):1842-1844.
20. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577-589.
21. Baron R, Kneissel M. WNT signalling in bone homeostasis and disease: from human mutations to treatments. Nature Medicine 2013; 19 (2):179-192.
22. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mes-enchymal progenitors controls os-teoblast and chondrocyte differentia-tion during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739-750.
23. Glass DA , Bialek P, Ahn JD, Star-buck M, Patel MS, Clevers H et al. Canonical Wnt signaling in differenti-ated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8(5):751-764.
24. Wei W, Zeve D, Suh J M, Wang X, Du Y, Zerwekh JE. Biphasic and Dos-age-Dependent Regulation of Osteo-clastogenesis by β-Catenin. Mol Cell Biol. 2011;31: 4706–4719.
25. Savvidou I, Khong T, Spencer A.
26. Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, Carrasco DE, Zheng M, He H, Tai Y-T, Mitsiades C, Anderson KC, Carrasco DR. Tar-geting the β-catenin/TCF transcrip-tional complex in the treatment of multiple myeloma. PNAS 2007; 104 (18): 7516-21.
27. Kocemba KA, Groen RWJ, van An-del H, Kersten MJ, Mahtouk K, Spaargaren M, Pals ST. Transcrip-tional silencing of Wnt-antagonist DKK1 by promoter methylation is as-sociated with enhanced Wnt signalling in advanced multiple myeloma. PLoS ONE 2012; 7 (2):e30359.
28. Chim CS, Pang R, Fung TK, Choi CL, Liang R. Epigenetic dysregulation of Wnt signalling pathway in multiple myeloma. Leukemia 2007;21:2527-36.
29. Van Andel H, Ren Z, Koopmans I, Joosten SPJ, Kocemba KA, de Lau W, Kersten MJ, de Bruin AM, Guikema JEJ, Clevers H, Spaargaren M, Pals ST. Aberrantly expressed LGR4 em-powers Wnt signalling in multiple myeloma by hijacking osteoblast-derived R-spondins. PNAS 2017; 114(2):376-381.
30. Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN, Aar-son SA. Canonical and noncanonical Wnts use a common mechanism to ac-tivate completely unrelated corecep-tors. Genes & Development 2010; 24: 2517-30.
31. Tung EK-K, Wong BY-C, Yau T-O, Ng IO-L. Upregulation of the Wnt co-receptor LRP6 promotes hepatocar-cinogenesis and enhances cell inva-sion. PLoS ONE 2012; 7(5):e36565.
32. Liua C-C, Priorb J, Piwnica-Wormsb D, Bua G. LRP6 overexpression de-fines a class of breast cancer subtype and is a target for therapy . PNAS 2010; 107 (11): 5136–41.
33. Qiang Y-W, Endo Y, Rubin JS, Rudikoff S. Wnt signalling in B-cell neoplasia. Oncogene 2003;22:1536-45.
34. Cruciat C-M, Niehrs C. Secreted and transmembrane Wnt inhibitors and ac-tivators. Cold Spring Harb Perspect Biol 2013;5:a015081.
35. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD. The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma. N Engl J Med. 2003;349:2483-2494.
36. Kaiser M, Mieth M, Liebisch P, Ober-lander R, Rademacher J, Jakob C, Kleeberg L, Fleissner C, Braendle, E, Peters M, Stover D, Sezer O, Heider U. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. European J Haematol. 2008;80(6): 490-494.
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