Drug Resistance Mechanisms in Cancer: Genetic and Epigenetic Drivers

Drug resistance represents a major obstacle in cancer treatment, contributing to therapeutic failure and disease recurrence. This review examines the molecular mechanisms underlying resistance to chemotherapy and targeted therapies, focusing on genetic alterations, epigenetic reprogramming, and cellular plasticity. Genetic drivers include mutations in oncogenes and tumour suppressor genes, amplification of drug efflux transporters, and alterations in DNA repair machinery. Epigenetic mechanisms encompass DNA methylation, histone modifications, and chromatin remodelling that collectively modulate drug sensitivity. Cell plasticity enables phenotypic transitions between drug-sensitive and resistant states through epithelial-mesenchymal transition and cancer stem cell characteristics. The tumour microenvironment further contributes to resistance through immunosuppression, metabolic reprogramming, and physical barriers to drug delivery. Understanding these multilevel mechanisms is crucial for developing combination therapies that can overcome or prevent resistance. This review synthesises current knowledge on resistance mechanisms and discusses emerging therapeutic strategies targeting these pathways.