Role of Wnt/β-catenin pathway in cancer drug resistance: Insights into molecular aspects of major solid tumors

Adaptive resistance to conventional and targeted therapies remains one of the major obstacles in the effective management of cancer. Aberrant activation of key signaling mechanisms plays a pivotal role in modulating resistance to drugs. An evolutionarily conserved Wnt/β-catenin pathway is one of the signaling cascades which regulate resistance to drugs. Elevated Wnt signaling confers resistance to anticancer therapies, either through direct activation of its target genes or via indirect mechanisms and crosstalk over other signaling pathways. Involvement of the Wnt/β-catenin pathway in cancer hallmarks like inhibition of apoptosis, promotion of invasion and metastasis and cancer stem cell maintenance makes this pathway a potential target to exploit for addressing drug resistance. Accumulating evidences suggest a critical role of Wnt/β-catenin pathway in imparting resistance across multiple cancers including PDAC, NSCLC, TNBC, etc. Here we present a comprehensive assessment of how Wnt/β-catenin pathway mediates cancer drug resistance in majority of the solid tumors. We take a deep dive into the Wnt/β-catenin signaling-mediated modulation of cellular and downstream molecular mechanisms and their impact on cancer resistance. [Display omitted] •Aberrant activation of Wnt/β-catenin pathway in cancer confers resistance to anticancer drugs.•Dysregulated Wnt/β-catenin pathway mediates cancer resistance against chemo-, targeted- and immuno-therapeutic drugs•Stem cell and microRNA-mediated cancer drug resistance have critical contribution from elevated Wnt/β-catenin pathway.•Crosstalk of β-catenin with other oncogenic pathways opens up an avenue of combination therapies to counter resistance.•Underlying molecular mechanisms reveal the need of novel advances to strategically counter drug resistance.