Decoding β-catenin associated protein-protein interactions: Emerging cancer therapeutic opportunities

The hyperactive Wnt/β-catenin signaling circuit has been proven to be closely related to the progression of various cancers, with β-catenin serving as a central regulator of pro-tumorigenic processes. Preclinical evidences strongly support β-catenin as a promising therapeutic target. However, it has long been considered “undruggable” due to challenges such as the lack of crystal structures for its N- and C-terminal domains, high mutation rates, and limited availability of inhibitors. Notably, the network of β-catenin-associated protein-protein interactions (PPIs) is vital in the progression of multiple diseases. These interactions form a cancer-specific network that participates in all phases of oncogenesis, from cell metastasis to immunosuppressive microenvironment formation. Thus, researches on these PPIs are essential for unraveling the molecular mechanisms behind tumors with aberrant β-catenin activation, as well as for developing new targeted therapies. In this review, we delve into how β-catenin's PPIs orchestrate cancer progression and highlight biological and clinical dilemmas, proposing frontier technologies and potential challenges in targeting β-catenin for cancer therapy.