Wnt/β-catenin mediated signaling pathways in cancer: recent advances, and applications in cancer therapy

Abstract

The Wnt/β-catenin signaling pathway is a highly conserved signaling pathway closely linked to cancer development through various biological processes, including oncogenic transformation, genomic instability, cancer cell proliferation, stemness, metabolism, cell death, immune regulation, and metastasis. Notably, its activation plays a crucial role in drug resistance to chemotherapy, targeted therapy and immunotherapy. Recent advances in drug development have identified several targeted inhibitors acting at key nodal points of this pathway, with some demonstrating synergistic efficacy when combined with immunotherapeutic agents. This review provides a comprehensive analysis of current understanding regarding the Wnt/β-catenin pathway in malignancy, emphasizing its multifaceted roles in tumor initiation, therapeutic resistance, and immune regulation. Additionally, we summarized the clinical performance of combination therapies targeting the Wnt/β-catenin pathway in conjunction with chemotherapy, targeted therapy, and immunotherapy. Although clinical development remains at a relatively early stage, pharmacological modulation of Wnt/β-catenin signaling offers considerable potential as a novel therapeutic paradigm in precision oncology.

Keywords: Cancer; Combined therapy; Immunotherapy; Targeted therapy; Wnt/β-catenin signaling pathway.

Fig. 1

The mechanism of canonical Wnt pathway. The Wnt/β-catenin signaling pathway plays a crucial role in normal physiological conditions, both in the presence and absence of the Wnt signal. In the absence of an extracellular canonical Wnt signal (Wnt off), the intracellular protein dishevelled (Dvl) remains inactive. Consequently, the β-catenin “destruction complex”, comprising APC, CK1α, GSK3β, and Axin, facilitates the phosphorylation of β-catenin. This phosphorylated β-catenin is then ubiquitinated and degraded through the action of the E3-ubiquitin ligase β-TRCP. In the nucleus, the transcription factors TCF/LEF function as transcriptional repressors of downstream genes by binding to Groucho/TLE. Conversely, when the canonical Wnt signal is present (Wnt on), it is recognized by the frizzled (Fzd) receptor and its co-receptor LRP5/6, forming a ternary complex. The intracellular domain of Fzd subsequently recruits Dvl, which promotes the phosphorylation of LRP6 and facilitates the recruitment and inhibition of Axin and GSK3β. As a result, the β-catenin “destruction complex” failes to form, allowing β-catenin to accumulate and translocate to the nucleus. In the nucleus, β-catenin competes Groucho/TLE for binding to TCF/LEF, thereby initiating the transcription of downstream target genes

Fig. 2

The mechanism of non-canonical Wnt signaling pathways. The mechanism of non-canonical Wnt/β-catenin pathway under normal physiological condition, involves the non-canonical Wnt signaling. The Wnt/Ca²⁺ pathway is initiated by the interaction between Wnt5a and frizzled (Fzd), leading to increased Ca²⁺ mobilization through the activation of protein kinase G (PKG) and inhibition of phospholipase C (PLC). This rise in Ca²⁺ signaling subsequently activates two Ca²⁺-sensitive enzymes: Ca²⁺/calmodulin-dependent protein kinase II (CamKII) and protein kinase C (PKC). CamKII can stimulate the TAK1-NLK pathway and modulate canonical Wnt signaling, while PKC influences the morphology of the F-actin cytoskeleton. Elevated Ca²⁺ levels can also activate the calcineurin/NFAT pathway, resulting in the activation of NF-κB. Additionally, the Wnt/planar cell polarity (PCP) pathway is initiated by the binding of a non-canonical Wnt ligand to Fzd, leading to the activation of downstream rho-associated protein kinase (ROCK). This activation affects the cytoskeleton by promoting actomyosin contractility and protrusion collapse. Furthermore, the downstream JNK/JUN pathway can be activated to modulate actin cytoskeleton organization

Fig. 3

The role of Wnt/β-catenin signaling pathway in cancer development and drug resistance. This figure elucidates the molecular components and mechanisms discussed in Part 2, focusing on the role of the Wnt/β-catenin signaling pathway in cancer development. A It provides an overview of how Wnt/β-catenin signaling facilitates tumorigenesis and malignant behaviors through various mechanisms. The dark red layer highlights specific mechanisms that drive tumor progression within each pathway. As indicated in the legend, molecules located on the outer layer with yellow or blue backgrounds represent upstream or downstream regulators of the pathway, respectively. Molecules that promote or inhibit Wnt signaling, or are upregulated/downregulated by activated Wnt signaling, are denoted in red and blue text. B This section illustrates the functional locus of molecules interacting with the Wnt/β-catenin signaling via different mechanisms, excluding those related to immunotherapy resistance. The left panel summarizes molecules with mechanisms that remain unclear within the pathway. The color coding for text and backgrounds is consistent with Panel A. C This panel delineates the mechanisms by which Wnt pathway-associated molecules contribute to immunotherapy resistance, maintaining the color schemes for text and backgrounds as established in Panel A

Fig. 4

Therapeutic strategies of targeted drugs in Wnt/β-catenin signaling pathway. In recent years, several components of the Wnt/β-catenin signaling pathway have been identified as promising therapeutic targets. These include: (1) PORCN inhibitors, which target PORCN, an O-acyltransferase that disrupts the receptor-binding process of Wnt by inhibiting the palmitoylation of the hairpin-2 motif; (2) Fzd inhibitors, which bind the cysteine-rich domain of Fzd receptors with an immunoglobulin Fc domain, thereby competing with the native Fzds for ligands and antagonizing Wnt signaling; (3) LRP5/6 inhibitors, which function either through Dkk1, an endogenous repressor of LRP and Fzd-related protein, or by directly antagonizing LRP5/6; (4) Axin stabilizer, which inhibit via tankyrase, a family of enzymes that promote Axin degradation via the ubiquitin–proteasome pathway; (5) CBP inhibitors, which block the interaction between CBP and β-catenin, where CBP acts as a co-activator of Wnt/β-catenin-mediated transcription; and (6) iCRTs, which directly bind to the TCF binding site on β-catenin

Fig. 5

Timeline of clinical trials of drugs targeting Wnt/β-catenin signaling pathway. This figure illustrates Part 5: Clinical applications of drugs targeting the Wnt/β-catenin signaling pathway, emphasizing the advancement of clinical trials for these pharmacological agents. Dates in black text denote the initiation of the trials, whereas dates in red text signify the publication of the initial clinical trial results. Notably, a portion of these trials has yet to release their findings