HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

SIMPLE SUMMARY: Tumor heterogeneity promotes the development of drug resistance in cancer. HDAC inhibitors modulate several processes that contribute to intra-tumoral heterogeneity. With careful consideration of the underlying biology, HDAC inhibitors can be utilized to improve therapeutic efficacy. ABSTRACT: Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.