Drug Resistance in Cancer: A Conceptual Shift from Single-Gene Mechanisms to Systemic Adaptive Resistance
This review proposes reframing multidrug resistance (MDR) from conventional single-gene mechanism models toward systemic adaptive resistance as a complex and evolving biological phenomenon, and systematically reviews classical resistance mechanisms (drug uptake/efflux, compensatory pathway activation, apoptosis evasion), non-genetic resistance mechanisms (drug-tolerant persisters, DTPs; epithelial-mesenchymal transition, EMT; cancer stem cell, CSC, plasticity and related factors), how interactions among these mechanisms contribute to tumor persistence and MDR evolution, and translational barriers together with emerging pharmacological strategies including longitudinal molecular monitoring and artificial intelligence (AI)-assisted drug resistance prediction.