Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Abstract

Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

Targeting Wnt signaling pseudokinases in hematological cancers

“…Wnt signaling is important for embryonic development and adult tissue homeostasis, and these distinct functions are mediated by a plethora of intracellular signaling cascades divided into two main categories: canonical and non‐canonical Wnt pathways . Canonical Wnt signaling promotes the β‐catenin‐dependent TCF/LEF (T‐cell factor/lymphoid enhancer‐binding factor) pathway or β‐catenin independent Wnt/STOP (Wnt/stabilization of proteins) signaling through Frizzled and LRP5/6 (low‐density lipoprotein receptor‐related proteins 5/6) receptors to mainly regulate cell differentiation and proliferation . On the other hand, the non‐canonical Wnt pathway is driven by the engagement of Frizzled, RORs, PTK7/CCK4, and RYK, via activation of Dishevelled (DVL)‐dependent RhoA/Rac1 GTPases of planar cell polarity (Wnt/PCP) signaling, G protein‐coupled receptor (GPCR) signaling, and RTK‐dependent PI3K‐AKT and YAP/TAZ (Yes‐associated protein/transcriptional coactivator with PDZ‐binding motif) signaling to regulate cell polarity, adhesion, and motility .…”

CDK 1‐mediated BCL 9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling

“…The physiological role of Wnt/stabilisation of proteins (STOP) signalling has been reported in early Xenopus embryogenesis and in epididymal sperm maturation (Huang et al, 2015;Koch et al, 2015). Recently, the potential cancer-associated roles of this signalling have also been suggested (Chen et al, 2017;Katoh & Katoh, 2017). One implicated oncogenic role of mitotic Wnt signalling is to stabilise proteins, some of which are prominent oncogenic drivers, such as c-Myc, cyclin D1 or b-catenin (Acebron et al, 2014).…”

Possible repurposing of pyrvinium pamoate for the treatment of mesothelioma: A pre‐clinical assessment

“…Therefore, the observed AXIN2 down‐regulation is indicative of Wnt pathway inhibition. We also analyzed the expression of ROR2 , an important mediator of the β‐catenin‐independent non‐canonical Wnt pathway (Katoh & Katoh, , ), and observed its down‐regulation upon pyrvinium pamoate treatment. ROR2 is recently emerging as a new target for anti‐cancer therapeutic intervention, owing to its expression in several cancers, in which it strongly correlates with more aggressive disease states (Debebe & Rathmell, ; Yang et al, ).…”