Critical Contribution of Various Signaling Pathways in the Development of Drug Resistance in Colorectal Cancer: An Update.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, with drug resistance being a major challenge in limiting the available treatment options. This review focuses on the signaling pathways (Hedgehog, Hippo, Notch, Wnt/β-catenin, PI3K/Akt, and MAPK/ERK pathways) that are implicated in the development of drug resistance mechanisms in CRC, such as DNA repair systems, tumor microenvironments, autophagy, metabolic reprogramming, evasion of apoptosis, and efflux pumps. Furthermore, recent advancements in targeted and combinatorial diagnostic-therapeutic approaches are highlighted. This review delineates the significance of signaling cascades and their clinical relevance, offering novel perspectives on the formulation of therapeutic strategies to mitigate drug resistance. In light of the increasing prevalence of drug-resistant CRC and the lack of effective solutions, it addresses the persistent demand for improved therapeutic modalities and provides a comprehensive framework for forthcoming research in this domain.