Non-canonical Wnt signaling pathway (Non-canonical Wnt pathway)

Non-canonical Wnt signaling pathways represent a diverse group of β-catenin-independent signal transduction cascades that are essential for coordinating cell polarity, migration, and organogenesis (Komiya and Habas, 2008). These pathways are primarily categorized into the Wnt/Planar Cell Polarity (PCP) pathway, which activates Rho GTPases and c-Jun N-terminal kinase (JNK) to reorganize the actin cytoskeleton, and the Wnt/Calcium pathway, which triggers intracellular calcium release and activates protein kinase C (PKC) and NFAT (Niehrs, 2012). Unlike the canonical Wnt pathway, these cascades do not rely on the stabilization of β-catenin or the activation of TCF/LEF transcription factors. In oncogenesis, non-canonical Wnt signaling, particularly mediated by ligands like Wnt5a and receptors like ROR1 or ROR2, is frequently hijacked to promote epithelial-mesenchymal transition (EMT), tumor invasion, and metastasis (Giles et al., 2003). Therapeutic targeting of these pathways is an active area of research, with agents such as the anti-ROR1 antibody cirmtuzumab (zilovertamab) showing clinical promise in treating hematologic and solid malignancies (Choi et al., 2018). However, drug development faces challenges due to the complex crosstalk between canonical and non-canonical Wnt branches and the potential for systemic toxicity given the pathway's role in normal tissue homeostasis (Kahn, 2014). Overall, the non-canonical Wnt pathway represents a complex network of interactions vital for structural organization and a key driver of aggressive cancer phenotypes.

Other names

β-catenin-independent Wnt signalingWnt/PCP pathwayWnt/Ca2+ pathwayWnt/planar cell polarity pathwayNon-canonical Wnt cascade

Inhibition of Wnt ligand binding to non-canonical receptors such as ROR1 or Frizzled, or modulation of ligand activity, thereby blocking β-catenin-independent downstream cascades including JNK activation, Rho GTPase signaling, and calcium mobilization (Choi et al., 2018; Niehrs, 2012).