Preclinical efficacy of the Wnt/β-catenin pathway inhibitor BC2059 for the treatment of desmoid tumors
A mutation in the *CTNNB1* gene, resulting in deregulation of the WNT/β-catenin pathway, is a common characteristic of desmoid tumors (DTs). While numerous β-catenin inhibitors have been tested in clinical trials, BC2059 (also known as Tegavivint), a selective inhibitor of nuclear β-catenin that binds to TBL-1, is the only one currently being studied specifically for the treatment of desmoid tumor patients. Preclinical research on BC2059 has shown efficacy in treating multiple myeloma, acute myeloid leukemia, and osteosarcoma. Our preclinical studies provide evidence of BC2059’s effectiveness in desmoid cell lines, offering valuable insights into its potential antitumor activity in desmoid tumor patients.
The in vitro effects of BC2059 were evaluated using desmoid tumor Tegatrabetan cell lines, while its ex vivo effects were assessed in an explant tissue culture model. Pharmacological inhibition of nuclear β-catenin by BC2059 significantly reduced cell viability, migration, and invasion in mutated DT cells, with a lesser impact on wild-type DTs. The reduction in viability of mutated DT cells was attributed to apoptosis. BC2059 treatment decreased β-catenin-associated TBL1 levels in all mutated DT cells, leading to a reduction in nuclear β-catenin. Additionally, BC2059 treatment downregulated both mRNA and protein levels of *AXIN2*, a β-catenin target gene.
In conclusion, our findings suggest that inhibiting nuclear β-catenin with BC2059 could represent a promising therapeutic strategy for treating desmoid tumors, particularly in patients with *CTNNB1* mutations.