Drug resistance in cancer: Emerging mechanisms, translational barriers, and pharmacological strategies.

Abstract

Multidrug resistance (MDR) remains a major challenge in cancer treatment. MDR has been explained by single-gene mechanisms, such as overexpression of ATP-binding cassette (ABC) transporters, drug-target mutations, activation of bypass signaling pathways, and increased DNA repair. However, these mechanisms alone are insufficient to explain the heterogeneity, reversibility, temporal evolution, and environmental dependence of drug resistance observed in clinical settings. Increasing evidence suggests that MDR is better viewed as a complex and evolving biological phenomenon rather than the result of isolated molecular events. This shift in perspective presents both challenges and opportunities for drug development. Future strategies will therefore require dynamic and mechanism-informed approaches that integrate rational drug combinations with sequential, intermittent, or adaptive treatment according to the evolving resistance state. In this review, we propose a conceptual shift from conventional MDR models toward systemic adaptive resistance. We review classical drug resistance, including drug uptake/efflux, compensatory pathway activation, and apoptosis evasion. We explore non-genetic drug resistance, such as drug-tolerant persisters (DTPs), epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) plasticity, and related factors. Then, we discuss the interaction between these mechanisms, and how their coordinated effects contribute to tumor persistence and the evolution of MDR. Finally, we evaluate barriers in translational medicine and emerging pharmacological strategies, including longitudinal molecular monitoring and artificial intelligence (AI) -assisted drug resistance prediction.