Dual Disruption: Targeting Mitotic Processes and Epigenetic Regulation to Overcome Anticancer Drug Resistance

Drug resistance is a considerable challenge to the existing cancer therapy resulting in disease reappearance and progression despite initial treatment success. The disruption of mitotic and epigenetic regulatory networks represents an innovative approach for cancer therapy. Mitotic regulators, including Aurora kinases (AURKA), Polo-like kinases (PLKs), and kinesins, are essential for chromosomal segregation for the development of newer progeny cells during the cell cycle process. However, it is a highly complex process and its dysregulation results in aneuploidy and intratumoral heterogeneity responsible for cancerous growth. Parallelly, epigenomic alterations by dysfunctional histone deacetylases (HDAC), DNA methyltransferases, and bromodomain and extra-terminal (BET) proteins result in modified chromatin architecture. Responsible for stemness, immunological evasion, and phenotypic plasticity. The association of these two processes of cell division results in the survival of cancerous cells. Epigenetic flexibility results in bypassing mitotic checkpoint failures by cancerous cells to modify epigenetic programming responsible for the evasion of therapeutic interventions. Combination therapies that target both pathways demonstrate enhanced cytotoxicity, extend the time before resistance manifests, and effectively eliminate drug-tolerant cancerous cells in aggressive cancers such as triple-negative breast cancer, glioblastoma, and hematological malignancies. This review highlights the therapeutic innovation offered by dual disruption, where the combination of targeting mitotic fidelity and epigenetic plasticity creates a vulnerability that is not possible through separate treatments. The combination of inducing mitotic stress and at the same time preventing chromatin-based adaptive rewiring, this strategy limits the formation of drug-tolerant persistent.