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ANew Wave of Targeting `Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities. Cells 2023, 12, 1110 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12081110  \nAcademic Editors: Anitha K. Shenoy and Liya Pi  \nReceived: 31 January 2023  \nRevised: 3 April 2023  \nAccepted: 5 April 2023  \nPublished: 8 April 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Life Science, Gachon University, Seongnam 13120, Republic of Korea  \n2 Department of Health Sciences and Technology, GAIHST, Lee Gil Ya Cancer and Diabetes Institute, Incheon 21999, Republic of Korea  \n* [Correspondence: moonjongkim7@gachon.ac.kr](Correspondence: moonjongkim7@gachon.ac.kr); Tel.: +82-32-899-6112  \nAbstract: Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody–drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target `undruggable' Wnt signaling.  \nKeywords: Wnt signaling; 􀀌-catenin; targeted cancer therapy; PROTAC; antibody–drug conjugate (ADC); anti-sense oligonucleotide (ASO)  \n1. Wnt Signaling Pathway  \nIn the early 1980s, Wnt signaling was first discovered when wingless, an essential developmental gene of Drosophila, was found [1] . Concurrently, Int-1, a mammalian wingless homolog, was identified as a driver gene for malignancy when its transcriptional activation was induced by the murine mammary tumor virus [2] . Through wingless and Int-1, a portmanteau name of `Wnt' was created. Over the four decades since its discovery, Wnt-mediated signaling has been extensively studied, revealing its evolutionarily conserved roles in regulating diverse cellular processes, including embryonic development, tissue homeostasis, and cell fate determination [3] .  \nWnt signaling consists of Wnt ligands, frizzled receptors (FZD family), co-receptors,􀀌-catenin destruction complexes, 􀀌-catenin/transcriptional partners, and other modulating components [3] . Wnt is a secreted ligand and mediates autocrine and paracrine signal transduction through its receptors and downstream effectors [4] . The intracellular downstream signaling of Wnt ligands/receptors is broadly divided into 􀀌-catenin-dependent signaling (a","cbCaikNXcB7j5ztp","https://ap.wps.com/l/cbCaikNXcB7j5ztp","pdf",2999143,23,"English","# Wnt Signaling Pathway\n## Wnt Ligands and Receptors","[{\"question\":\"Why is targeting Wnt signaling considered challenging in cancer therapy?\",\"answer\":\"Wnt signaling plays pleiotropic roles in development, tissue homeostasis, and stem cells, so inhibition often causes concomitant side effects. In addition, the cascade complexity varies across cancer contexts, hindering optimized targeted therapy development.\"},{\"question\":\"What motivates Wnt-targeted therapies despite current lack of clinical availability?\",\"answer\":\"Preclinical studies show that inhibiting Wnt signaling robustly suppresses tumor development across multiple in vivo models, and many Wnt-targeted therapies have been investigated over the past decades.\"},{\"question\":\"What newer strategies does the review highlight for targeting 'undruggable' Wnt signaling?\",\"answer\":\"It emphasizes new waves of Wnt targeting combining recently developed technologies such as PROTAC/molecular glue, antibody–drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may enable new clinical opportunities.\"}]","A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy - Review | PDF",1790257483,58]