Dual targeting of YAP1 and β-catenin: a therapeutic strategy for colorectal cancer

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, driven in part by signaling plasticity and adaptive resistance to therapy. Two pathways that play central and interconnected roles in CRC progression are the Hippo pathway effector Yes-associated protein 1 (YAP1) and the canonical Wnt/β-catenin cascade. Aberrant Wnt/β-catenin signaling, most frequently arising from APC mutations, sustains oncogenic transcriptional programs essential for proliferation and stem cell maintenance, while YAP1 activation, which is typically non-mutational, supports tumor growth, phenotypic plasticity, and therapy resistance. Accumulating evidence demonstrates that YAP1 and β-catenin function within an integrated oncogenic network, in which reciprocal reinforcement and compensatory signaling limit the durability of single-pathway inhibition. This review synthesizes current knowledge on Hippo-Wnt pathway convergence in CRC and critically evaluates emerging pharmacological and genetic strategies targeting YAP1 and β-catenin. We highlight preclinical/clinical data showing that coordinated inhibition of both pathways more effectively suppresses cancer stemness, restores apoptotic sensitivity, and overcomes adaptive resistance compared with monotherapy. Recent advances including YAP-TEAD disruptors, β-catenin transcriptional modulators, targeted protein degraders, and RNA-based approaches, provide a mechanistic rationale for rational combination regimens. Collectively, these findings support dual targeting of YAP1 and β-catenin as a strategy to counteract signaling redundancy and improve therapeutic durability in molecularly defined CRC subsets, warranting further translational and clinical investigation.