Abstract
Background: Drug resistance remains a primary obstacle to effective cancer therapy, compromising both clinical response and long-term prognosis. The evolutionarily conserved Wnt signaling pathway is frequently implicated in tumor survival, proliferation, and therapeutic escape. This review aims to provide an updated synthesis of the role of Wnt signaling in cancer drug resistance and evaluate its potential as a therapeutic target.
Methods: We conducted a narrative review of the current literature by searching electronic databases (e.g., PubMed, Scopus, and Web of Science) for studies focusing on the interplay between Wnt signaling and mechanisms of chemo- and targeted-therapy resistance. Eligible studies were analyzed to synthesize current insights into Wnt-mediated resistance patterns and emerging therapeutic strategies.
Results: Wnt signaling acts as a central nexus in driving resistance through diverse, often overlapping, mechanisms, including the promotion of cancer stem cell plasticity, enhanced DNA damage repair, evasion of apoptosis, and the regulation of oncogenic ncRNAs. While Wnt pathway inhibition represents a promising therapeutic avenue, its clinical translation has been challenged by issues regarding toxicity, limited specificity, and tumor heterogeneity. Current efforts to overcome these barriers focus on direct Wnt blockade, combination regimens with standard chemotherapies, and integration into immunotherapy or other targeted therapies. Furthermore, genomic and transcriptomic profiling shows promise in predicting resistance patterns, thereby facilitating more personalized, tailored interventions.
Conclusion: Although Wnt signaling is a critical driver of therapeutic resistance, successful clinical targeting requires overcoming intrinsic biological complexities. Future strategies should prioritize precision medicine approaches, integrating multi-omics data to refine patient selection and optimize combinatorial therapeutic regimens to improve patient outcomes.