Frizzled-8 (FZD8)

Frizzled-8 (FZD8) is a seven-transmembrane domain receptor that belongs to the Frizzled family, serving as a critical component of the Wnt signaling pathway (UniProt: P26294). It primarily mediates canonical Wnt signaling by binding to Wnt ligands and interacting with the LRP5/6 co-receptors, which leads to the stabilization of β-catenin and the activation of genes involved in cell proliferation and stem cell maintenance (PMID: 25135933). FZD8 is frequently upregulated in various cancers, including pancreatic and lung carcinomas, where it contributes to tumor growth, epithelial-to-mesenchymal transition, and resistance to standard therapies (PMID: 29739774). Therapeutic targeting of the FZD8-Wnt interaction has been explored through the development of monoclonal antibodies like Vantictumab and decoy receptors like Ipafricept (FZD8-Fc fusion protein), which aim to sequester Wnt ligands and prevent receptor activation (PMID: 28223404). Despite promising preclinical activity, clinical development has been complicated by significant on-target toxicities, most notably the disruption of bone homeostasis leading to decreased bone mineral density and increased fracture risk (PMID: 27573421).

Other names

Frizzled class receptor 8Fz-8Fz8Frizzled-8 receptorWnt receptor Frizzled-8

Antagonism of Wnt ligand binding to the Frizzled-8 receptor or sequestration of canonical Wnt ligands (such as Wnt1, Wnt3a, and Wnt8) using a decoy receptor to inhibit downstream β-catenin-dependent signaling (PMID: 28223404).