Tegavivint, a first-in-class TBL1 inhibitor demonstrates potent activity in WNT-driven colorectal cancers

Background. Tegavivint is a clinical phase investigational small molecule that disrupts Wnt/beta-catenin signaling by targeting transducing beta-like protein 1 (TBL1), a critical mediator of nuclear beta-catenin transcriptional activity. Unlike upstream Wnt inhibitors, tegavivint selectively impairs oncogenic transcriptional programs while sparing physiological Wnt functions, minimizing systemic toxicity. Preclinical studies and early-phase clinical trials have demonstrated that tegavivint suppresses tumor growth and enhances immune infiltration across multiple cancer models, including hepatocellular carcinoma and non-small cell lung cancer. Mechanistically, tegavivint promotes degradation of nuclear beta-catenin, downregulates Wnt target gene expression, and modulates the tumor immune microenvironment. This mode of action is particularly relevant in colorectal cancer (CRC), where aberrant Wnt signaling, frequently driven by APC or CTNNB1 mutations, plays a central role in tumorigenesis. The present study investigates the potential therapeutic efficacy of tegavivint in CRC. Methods. To evaluate the cytotoxic potential of tegavivint in CRC, we conducted the Broad PRISM screen. Annexin V analysis revealed dose- and time-dependent induction of apoptosis. To further elucidate the molecular consequences of treatment, transcriptomic profiling was performed in HCT15 cells. To investigate the influence of the tumor microenvironment on drug sensitivity, dose-response analyses were extended to CRC organoid models, including cell line-derived organoids co-cultured with fibroblasts, as well as patient-derived organoids (PDOs) containing endogenous stromal components. Last, Tegavivint was investigated in a combination drug screen to identify mechanisms of activity and potential synergies in 2D cells and PDOs. Results. Tegavivint monotherapy exhibited robust antitumor activity across a spectrum of CRC preclinical models, including 2D cell lines, 3D spheroids, PDOs. RNA-seq analysis revealed marked transcriptional repression of Wnt/beta-catenin signaling interacting genes along with induction of apoptotic programs, confirming the reprogramming of Wnt/b-catenin signaling and subsequent cell death by tegavivint. Furthermore, Tegavivint treatment induced apoptosis in responsive models, validating our initial mechanistic predictions and supporting its role as a targeted therapeutic agent in WNT-driven CRC. Tegavivint demonstrated synergistic activity when combined with VEGF-TKIs and pan-RAS inhibitors, while combination with other Wnt-inhibitors yielded no added activity. Conclusion. These findings underscore the translational promise of Tegavivint as a therapeutic strategy in colorectal cancer, supporting its advancement toward clinical development to improve outcomes in WNT-driven disease subsets.