Post-transcriptional regulation in cancer chemoresistance

Cancer remains the second leading cause of death worldwide, surpassed only by cardiovascular diseases. Although cancer-specific mortality rates have declined due to advances in early detection and therapeutic strategies, the absolute number of cancer-related deaths continues to rise, driven by increasing disease incidence associated with population aging and lifestyle factors. A substantial proportion of cancer mortality is attributable to the development of resistance to anticancer therapies, making drug resistance a critical barrier to durable treatment efficacy and a major focus for clinical and translational research. Drug resistance arises from a wide spectrum of molecular and microenvironmental adaptations that enable cancer cells to limit drug uptake, neutralize or bypass drug activity, and evade therapy-induced cell death. These adaptive processes are orchestrated by extensive rewiring of gene expression programs, regulatory networks, and signaling pathways, ultimately reshaping cellular metabolism and stress responses. Traditionally, such adaptations have been primarily ascribed to genetic alterations and transcriptional reprogramming. However, growing evidence indicates that posttranscriptional regulatory mechanisms play a pivotal and previously underappreciated role in modulating gene expression and protein activity during the acquisition of drug-resistant phenotypes. RNA-mediated mechanisms, including regulation of mRNA stability, translation, subcellular localization, and RNA-protein interactions, introduce a dynamic and reversible level of control over protein expression and activity. In particular, non-canonical RNA-binding proteins, diverse classes of non-coding RNAs, and riboregulatory mechanisms have emerged as critical modulators of pathways involved in drug transport, DNA damage response, apoptosis, and metabolic adaptation. These processes allow cancer cells to rapidly fine-tune functional proteomes without requiring permanent genetic changes, thereby facilitating phenotypic plasticity and therapeutic escape. In this review, we summarize recent advances in the field, with a particular emphasis on emerging posttranscriptional mechanisms of gene regulation that contribute to anticancer drug resistance. By highlighting the dynamic and multilayered nature of RNA-mediated regulatory processes, we aim to provide a comprehensive framework for understanding how cancer cells adapt to therapeutic pressure and to identify novel avenues for therapeutic intervention in the context of drug-resistant disease.