Targeting JOSD2 degrades β-catenin to suppress colorectal cancer metastasis by disrupting RAS/ERK/β-catenin axis.

PRDX1 drives colorectal cancer progression and immune microenvironment remodeling by facilitating PRMT5 nuclear translocation to activate Wnt/β-catenin signaling.

Findings identify a novel PRDX1-PRMT5 axis that activates Wnt/β-catenin signaling, highlighting a potential therapeutic strategy for CRC by targeting this pathway to suppress tumor progression and remodel the immune microenvironment.

MICAL2 as a key effector of β-catenin signaling driving melanoma progression and therapeutic resistance.

It is demonstrated that activation of β-catenin is associated with a poor prognosis in melanoma and inhibiting the enzymatic activity of MICAL2 offers a promising and innovative strategy to improve outcomes in β-catenin-driven melanoma.

Abstract B069: Pharmacodynamic evidence of Wnt/β-catenin inhibition by tegavivint, a TBL1-directed transcriptional modulator, in advanced hepatocellular carcinoma: a phase 1 study

Wnt/β-catenin pathway activation is a hallmark of many cancers, with Wnt pathway mutations present in ∼40% of advanced HCC (aHCC). TBL1 functions as a central scaffold and chromatin-state regulator within the TCF/β-catenin transcriptional machinery and controls degradation of nuclear b-catenin and is required for assembly of the active transcriptional complex, promoting oncogenic Wnt signaling. Tegavivint is a first-in-class small-molecule inhibitor of TBL1, discovered in a chemical genomics screen as an inhibitor of β-catenin transcriptional activity. Binding of TBL1 by tegavivint disrupts theTBL1/β-catenin complex, resulting in selective degradation of nuclear β-catenin while preserving cytoplasmic and membrane-bound β-catenin functions associated with normal tissue homeostasis. This mechanism inhibits Wnt-driven oncogenicity while avoiding toxicities observed with upstream Wnt inhibitors, representing a novel downstream approach to targeting the Wnt pathway. Tegavivint has been evaluated in a phase 1/2 dose escalation study in advanced hepatocellular carcinoma (NCT05797805) in which the drug was well tolerated and demonstrated clinical responses in a heavily pre-treated population harboring Wnt-pathway mutations. Here, we present an integrated analysis of preclinical and clinical pharmacodynamic (PD) data characterizing tegavivint activity. Tumor mutational status was correlated with clinical status and patient outcomes. Clinical benefit was observed only in patients with mutations in the Wnt pathway genes, CTNNB1, AXIN1, APC, and CREBBP. Transcriptional signatures of tegavivint were analyzed by RNA-seq, demonstrating downregulation of Wnt/β-catenin target genes and induction of apoptotic pathways, consistent with transcriptional reprogramming via TBL1-mediated inhibition of β-catenin activity. Clinical pharmacodynamic effects were evaluated by IHC of paired tumor biopsies, which revealed reductions in active β-catenin following treatment, supporting on-target activity. Serum biomarker analysis showed modulation of Wnt-regulated proteins, including decreases in DKK1, FGF-2, MMP-1, PDGF-AA, and VEGF-A. These PD changes mirror those observed in desmoid tumor patients treated with tegavivint (NCT03459469), indicating mechanism-based biomarker changes across tumor types. The concordance of transcriptional, tissue-based, and circulating biomarkers provides compelling evidence of on-target inhibition of the TBL1/β-catenin transcriptional complex. Collectively, these findings establish TBL1 as a clinically actionable regulator of oncogenic transcription and demonstrate that tegavivint achieves pharmacodynamic modulation of the Wnt pathway through a differentiated downstream mechanism. This approach represents a novel strategy for targeting Wnt-driven cancers. Aundrietta D. Duncan, Elena Ramirez, Julissa Simmons, Mahtab Youseffi, David D. Stenehjem, Stephen K. Horrigan. Pharmacodynamic evidence of Wnt/β-catenin inhibition by tegavivint, a TBL1-directed transcriptional modulator, in advanced hepatocellular carcinoma: a phase 1 study [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B069.

CAF-derived TGF-β1 activates an LBH-mediated β-catenin stabilization program to drive gastric cancer progression

Aberrant Wnt/β-catenin signaling is frequently observed in gastric cancer (GC); however, the mechanisms sustaining this pathway in the absence of canonical genetic mutations remain incompletely understood. Here we show that the transcriptional cofactor LBH drives mutation-independent Wnt activation and malignant progression in GC via a tumour microenvironment-regulated post-translational stabilization mechanism. By integrating single-cell transcriptomics with multicentre clinical cohorts, we identify LBH as a principal regulator of epithelial–mesenchymal transition and peritoneal metastasis, and its elevated expression independently predicts poor patient survival. Mechanistically, fi broblast activation protein (FAP)-positive cancer-associated fi broblasts (CAFs) secrete TGF-β1, which selectively induces LBH expression in adjacent GC cells via the SMAD2/3 signaling cascade. Crucially, LBH physically interacts with β-catenin, providing steric hindrance that prevents destruction complex-mediated phosphorylation and subsequent ubiquitin-proteasomal degradation. This FAP⁺ CAF–TGF-β1–LBH–β-catenin paracrine axis continuously sustains global Wnt transcriptional output without requiring intrinsic genetic mutations. Our findings elucidate a critical tumour–stroma crosstalk mechanism and establish the targeted disruption of the LBH–β-catenin interaction interface as a clinically relevant therapeutic strategy for advanced gastric cancer.

RNF113A Promotes Colorectal Cancer Metastasis by Regulating TGF-β Pathway and EMT via Ubiquitin-Mediated Degradation of SNIP1.

Background RNF113A is a RING finger protein that is upregulated in colorectal cancer (CRC). Smad nuclear-interacting protein 1 (SNIP1) negatively regulates the transforming growth factor-beta (TGF-β) pathway in CRC and plays a significant role in disease progression; however, its precise regulatory mechanism remains unclear. Aims To investigate whether RNF113A is associated with SNIP1 protein stability and TGF-β pathway modulation in CRC and to explore the potential underlying molecular mechanisms. Study Design In vitro experimental study. Methods Immunohistochemistry and correlation analyses were performed on clinical CRC specimens to assess the expression relationships among RNF113A, SNIP1, and TGF-β1. CRC cell clonogenic capacity and migration were evaluated using colony formation, wound healing, and transwell assays. Co-immunoprecipitation was used to assess protein-protein interactions. Protein stability was examined via RNF113A overexpression and knockdown, with or without proteasome inhibition (MG132). TGF-β pathway-related protein expression and epithelial-mesenchymal transition markers were assessed by qPCR and Western blotting, using TGF-β1 (pathway activator) and SB525334 (ALK5 inhibitor) for pharmacological modulation. Results RNF113A expression was inversely correlated with SNIP1 and positively correlated with TGF-β1 in clinical specimens. Functionally, RNF113A promoted CRC cell clonogenic capacity and migration. Mechanistically, RNF113A interacted with SNIP1. RNF113A overexpression decreased SNIP1 protein levels, whereas RNF113A knockdown increased them. This effect was reversed by MG132, suggesting ubiquitin-proteasome-mediated degradation. Conclusion This study suggests that RNF113A is associated with SNIP1 ubiquitination and degradation, potentially modulating TGF-β signaling and CRC cell migration. These findings reveal a potential RNF113A/SNIP1/TGF-β regulatory axis and highlight RNF113A as a potential therapeutic target in CRC, warranting further mechanistic validation.

CircARHGAP10 inhibits colorectal cancer cell proliferation, migration and invasion by governing the miR-29a-5p/LPP axis and regulating Wnt/β-catenin signaling pathway.