Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors

Abstract

The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.

Keywords: Beta-catenin; Colorectal cancers; Gamma secretase; Hedgehog; Targeted therapy; Wnt.

Fig 1

The Wnt pathway can be classified as canonical and non-canonical. In the canonical pathway, Wnt signaling when it is on inhibits the degradation of β-catenin, which can regulate transcription of many genes. Wnt signaling is activated by binding of Wnt proteins to surface receptors composed of the seven transmembrane frizzled proteins and the LRP5/6. Upon binding, the cytoplasmic protein disheveled (Dvl) is activated. Activation of Dvl induces the dissociation of GSK-3β from Axin and leads to the inhibition of GSK-3β. Next, the phosphorylation and degradation of β-catenin is inhibited because of the inactivation of the “destruction complex”. Subsequently, stabilized β-catenin translocates into the nucleus leading to transcription of target genes like C-Myc and Cyclin D1. RNF43 (Ring finger protein 43) / ZNRF3 promote FZD receptor turnover. R-spondins or RSPO’s bind to RNF43/ZNRF3 causing their ubiquitination and clearance, resulting in increased cell surface FZD receptors.

Fig 2a

Canonical Wnt Pathway and Inhibitors of the Wnt/beta-Catenin Signaling Pathway schematic representation of the Canonical Wnt Pathway and pharmacologic inhibitors of the Wnt/beta-catenin signaling pathway.

Fig 2b

Non-Canonical Wnt Pathway and the Notch and Sonic Hedgehog Pathway-The two major non-canonical pathways are Wnt/calcium and Planar Cell Polarity (PCP) pathways. In the Wnt/calcium pathway, Wnt binding to Frizzled activates Dvl, causing calcium release from the endoplasmic reticulum, activating calcium-binding proteins including protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII). Signal transduction through Ca²⁺ activates the nuclear factor of activated T cells (NFAT). The Wnt/PCP pathway is mediated by the GTPases RhoA and Ras, which through the RhoA-Rho-associated kinase (ROCK) axis or JNK, can exert effects on the cytoskeleton. A schematic of the Notch and Sonic Hedgehog pathway is shown.

Fig 3

Cross-Talk between the Wnt, Notch and Sonic Hedgehog Pathways- Beta-catenin can drive activation of Notch signaling by increasing expression of the JAG1 gene, which encodes the Notch ligand Jagged1. Sfrp-1 may be a negative regulator for both SHH and Wnt/beta-catenin pathway.