Abstract
WNT/β-catenin signaling plays fundamental roles in numerous developmental processes and in adult tissue homeostasis and repair after injury, by controlling cellular self-renewal, activation, division, differentiation, movement, genetic stability, and apoptosis. As such, it comes as no surprise that dysregulation of WNT/β-catenin signaling is associated with various diseases, including cancer, fibrosis, neurodegeneration, etc. Although multiple agents that specifically target the WNT/β-catenin signaling pathway have been studied preclinically and a number have entered clinical trials, none has been approved by the FDA to date. In this chapter, we provide our insights as to the reason(s) it has been so difficult to safely pharmacologically target the WNT/β-catenin signaling pathway and discuss the significant efforts undertaken towards this goal.
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Abbreviations
- 17-AAG:
-
17-Allylamino-geldanamycin
- ALDH1:
-
Aldehyde dehydrogenase 1 family member A1
- AML:
-
Acute myeloid leukemia
- APC:
-
Adenomatous polyposis coli
- ApcMin:
-
Mutant allele Min (multiple intestinal neoplasia) of the murine Apc locus which predisposes to intestinal adenoma formation
- Arg1:
-
Arginase 1
- Arg2:
-
Arginase 2
- ASCO:
-
American Society of Clinical Oncology
- BCL-2:
-
BCL2 apoptosis regulator
- BCR–ABL:
-
Mutation that is formed by the combination of two genes, known as BCR (BCR activator of RhoGEF and GTPase) and ABL (ABL proto-oncogene 1, non-receptor tyrosine kinase)
- BIRC5:
-
Baculoviral IAP repeat containing 5 (also known as survivin)
- BMP:
-
Bone morphogenetic protein
- BRAF:
-
B-Raf proto-oncogene, serine/threonine kinase
- CAR-T:
-
Chimeric antigen receptor (CAR) T cells
- CBP:
-
CREB-binding protein
- Ccnd1:
-
Cyclin D1
- Ccnd3:
-
Cyclin D3
- CD133:
-
Prominin 1
- CD27:
-
CD27 molecule
- CD40:
-
CD40 molecule
- CD44:
-
CD44 molecule (Indian blood group)
- CD8A:
-
CD8a molecule
- CDK1:
-
Cyclin dependent kinase 1
- CDK2:
-
Cyclin dependent kinase 2
- CDK4:
-
Cyclin dependent kinase 4
- CDK6:
-
Cyclin dependent kinase 6
- CK1α:
-
Casein kinase 1 alpha
- CK20:
-
Keratin 20
- CKO:
-
Conditional knockout
- CLK:
-
CDC-like kinase
- CLK2:
-
CDC like kinase 2
- CLK3:
-
CDC like kinase 3
- c-Myc:
-
MYC proto-oncogene, bHLH transcription factor
- COMP:
-
Cartilage oligomeric matrix protein
- COX:
-
Cyclooxygenase
- CRC:
-
Colorectal cancer
- Cre:
-
Cre recombinase
- CreERT2:
-
Cre recombinase (Cre) fused to a mutant estrogen ligand-binding domain (ERT2) that requires the presence of tamoxifen for activity
- CSC:
-
Cancer stem cells
- CTLA4:
-
Cytotoxic T-lymphocyte associated protein 4
- Cxcl1:
-
C-X-C motif chemokine ligand 1
- Cxcl2:
-
C-X-C motif chemokine ligand 2
- CYCA2:
-
Cyclin A2
- DAB2:
-
Disabled homolog 2
- DKK1:
-
Dickkopf WNT signaling pathway inhibitor 1
- DVL:
-
Dishevelled segment polarity protein
- DYRK1A:
-
Dual specificity tyrosine phosphorylation-regulated kinase 1A
- EC50:
-
Concentration of a drug that gives half-maximal response
- EGCG:
-
Epigallocatechin 3 gallate
- ELISA:
-
Enzyme-linked immunosorbent assay
- EMT:
-
Epithelial-mesenchymal transition
- ETS:
-
Erythroblast transformation-specific
- FDA:
-
US Food and Drug Administration
- FGF:
-
Fibroblast growth factor
- fl/fl:
-
Homozygous for allele floxed (flanked by loxP sites)
- FLT3:
-
Fms related receptor tyrosine kinase 3
- Foxp3:
-
Forkhead box P3
- FZD:
-
Frizzled class receptor
- FZD1:
-
Frizzled class receptor 1
- FZD2:
-
Frizzled class receptor 2
- FZD5:
-
Frizzled class receptor 5
- FZD7:
-
Frizzled class receptor 7
- FZD8:
-
Frizzled class receptor 8
- GSK3:
-
Glycogen synthase kinase 3
- GSK3β:
-
Glycogen synthase kinase 3 beta
- hDVL1:
-
Human dishevelled segment polarity protein 1
- HGF:
-
Hepatocyte growth factor
- HGK:
-
Hematopoietic progenitor kinase/germinal center kinase-like kinase (also known as MAP4K4)
- hMSC:
-
Human mesenchymal stem cells
- HSC:
-
Hepatic stellate cells
- IC50:
-
Half-maximal inhibitory concentration
- iCRT:
-
Inhibitor of catenin responsive transcription (CRT)
- Ifng:
-
Interferon gamma
- IL10:
-
Interleukin 10
- IWP:
-
Inhibitor of WNT production
- IWR:
-
Inhibitor of WNT response
- JAK:
-
Janus kinase
- JAK3:
-
Janus kinase 3
- Kat3:
-
Lysine acetyltransferases type 3
- KD:
-
Dissociation constant
- Lef:
-
Lymphoid enhancer factor
- Lgr4:
-
Leucine rich repeat containing G protein-coupled receptor 4
- Lgr5:
-
Leucine rich repeat containing G protein-coupled receptor 5
- Lgr6:
-
Leucine rich repeat containing G protein-coupled receptor 6
- Lkb1:
-
Liver kinase B1 (also known as Stk11)
- LRP5:
-
LDL receptor-related protein 5
- LRP6:
-
LDL receptor-related protein 6
- MAPK:
-
Mitogen-activated protein kinase
- MET:
-
MET proto-oncogene, receptor tyrosine kinase
- MMTV:
-
Mouse mammary tumor virus
- NCK:
-
NCK adaptor protein
- NF-κB:
-
Nuclear factor-κB
- NMR:
-
Nuclear magnetic resonance spectroscopy
- Nrp1:
-
Neuropilin 1
- NSAIDs:
-
Non-steroidal anti-inflammatory drugs
- p300:
-
E1A binding protein p300
- p53:
-
Tumor protein p53
- PARP:
-
Poly(ADP-ribose) polymerase
- PARP 1:
-
Poly(ADP-ribose) polymerase 1
- PARP 2:
-
Poly(ADP-ribose) polymerase 2
- PD-1:
-
Programmed cell death 1 (also known as PDCD1)
- PDGFRα:
-
Platelet derived growth factor receptor alpha
- PD-L1:
-
Programmed cell death 1 ligand 1
- PDZ:
-
PDZ domain
- PGE2:
-
Prostaglandin E2
- PI3K:
-
Phosphatidylinositol 3-kinase
- Porcn:
-
Porcupine O-acyltransferase
- PTEN:
-
Phosphatase and tensin homolog
- RAR:
-
Retinoic acid receptor
- Rnf43:
-
Ring finger protein 43
- RSPO:
-
R-spondin
- RXR:
-
Retinoid X receptor
- SAM68:
-
SRC-associated in mitosis 68 kDa protein (also known as KHDRBS1)
- SRSF:
-
Serine and arginine rich splicing factor
- SSC:
-
Somatic stem cells
- Stat:
-
Signal transducer and activator of transcription
- Tcf:
-
T-cell factor
- TCF1:
-
T-cell factor 1
- TCF4:
-
T-cell factor 4
- Tcf7:
-
T-cell factor 7
- TGFβ:
-
Transforming growth factor beta
- TGFβ1:
-
Transforming growth factor beta 1
- THBS1:
-
Thrombospondin 1
- Tmax:
-
The time at which the maximum blood concentration of a drug is achieved after the drug has been administered and before the administration of a second dose
- TNIK:
-
TRAF2 and NCK-interacting kinase
- TNKS1:
-
Tankyrase 1
- TNKS2:
-
Tankyrase 2
- TRAF2:
-
TNF receptor associated factor 2
- Tregs:
-
Regulatory T cells
- TRKA:
-
Tropomyosin receptor kinase A
- US:
-
United States
- VDR:
-
Vitamin D receptor
- WNT1:
-
Wnt family member 1
- WNT3A:
-
Wnt family member 3A
- αSMA:
-
Actin alpha 2, smooth muscle
- β-CTX:
-
Beta C-terminal telopeptide
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Acknowledgements
The authors thank David P. Lin for assistance with illustrations/graphics. Keane K.Y. Lai has been supported by US National Institutes of Health (NIH) grant K08AA025112. Michael Kahn has been supported by City of Hope Comprehensive Cancer Center Support Grant NIH P30CA033572, NIH grants R01CA166161, R21NS074392, R21AI105057, and R01HL112638, and the Rotary Coins for Alzheimer’s Research Trust (CART).
Conflicts of Interest
Michael Kahn has an equity position in 3 + 2 Pharma.
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Lai, K.K.Y., Kahn, M. (2021). Pharmacologically Targeting the WNT/β-Catenin Signaling Cascade: Avoiding the Sword of Damocles. In: Schulte, G., Kozielewicz, P. (eds) Pharmacology of the WNT Signaling System. Handbook of Experimental Pharmacology, vol 269. Springer, Cham. https://doi.org/10.1007/164_2021_523
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