Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications

Histone deacetylase inhibitors (HDI) are a promising new approach to the treatment of cancer. HDIs have been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of transformed cell lines; inhibit tumor growth in animal models; and show antitumor activity in clinical trials. Vorinostat, which has shown clinical responses in similar to 30% of patients with advanced cutaneous T-cell lymphoma, is the first HDI approved for the treatment of cancer, and it is currently being evaluated in other indications. A better understanding of the molecular determinants of resistance to HDIs may provide the basis for therapeutic combinations with improved clinical efficacy. Poor response to treatment could be linked to systemic factors like pharmacokinetics or to tumor-specific factors both at the level of the malignant cells (tumor intrinsic) or the tumor microenvironment. This review focuses on the tumor intrinsic mechanisms of drug resistance (excluding mechanism of acquired resistance due to chronic exposure). In particular, attention is given to selected mechanisms that are relevant across chemical classes of HDIs and that can aid in the design of rational combination strategies.