Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

SIMPLE SUMMARY: Beyond mutations, epigenetic changes have been described as drivers for cancer as well. While leaving the overall DNA structure intact, they can be responsible for tumor malignancy by mediating the transcriptional upregulation of oncogenes. This provides the basis for “epigenetic therapies” in cancer. Histone deacetylases (HDACs) are major players in epigenetic reprogramming. HDAC inhibitors (HDACis), either with broad-spectrum activity on various HDAC isoforms or with specific subtype specificity, have shown promising anticancer efficacies. The tremendous number of genes potentially affected creates the possibility for the parallel targeting of multiple disease-relevant pathways. Here, we give a comprehensive overview of various preclinical and clinical studies on HDACis. A particular focus is placed on the detailed description of promising strategies based on the combination of HDACis with other drugs. This also includes the development of new bifunctional inhibitors as well as novel approaches for HDAC degradation, rather than inhibition, via PROteolysis-TArgeting Chimeras (PROTACs). ABSTRACT: The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).