HDAC Inhibitors in Cancer: Where They Work and Where They Do Not

A Broad Mechanism

There are 18 human HDACs in several classes. Inhibiting them raises histone acetylation and reactivates some silenced genes, but HDACs also deacetylate transcription factors, chaperones, tubulin and DNA-repair proteins, so the drugs have wide-ranging effects on protein function and stability.

In sensitive cancer cells this produces cell-cycle arrest, differentiation and apoptosis, partly through re-expression of pro-apoptotic and cell-cycle-inhibitor genes.

Approved Uses

Vorinostat and romidepsin are approved for cutaneous T-cell lymphoma, romidepsin and belinostat for peripheral T-cell lymphoma, and panobinostat has been used with bortezomib and dexamethasone in multiple myeloma. T-cell lymphomas appear unusually dependent on the pathways these drugs disturb.

Chidamide is approved in some countries for peripheral T-cell and breast cancer indications.

Limited Solid-Tumour Activity

Despite extensive testing, HDAC inhibitors have shown little single-agent activity in common solid tumours, and combination trials have often been limited by overlapping toxicity such as fatigue, cytopenias and cardiac effects.

The reasons are not fully understood but likely include the breadth of the mechanism and the lack of a predictive biomarker to select patients.

Newer Directions and Combinations

Interest has shifted toward isoform-selective HDAC inhibitors, which aim to keep the useful effects while reducing the fatigue and cytopenias of pan-HDAC inhibition. HDAC6-selective agents and the class I-selective drug entinostat have been tested this way, the latter mainly with endocrine therapy or immunotherapy in breast cancer, without yet changing standard care.

The strongest combination rationale is with hypomethylating agents in myeloid disease and with immune checkpoint inhibitors, since HDAC inhibition can increase tumour antigen presentation and alter the immune microenvironment. Results so far are mixed, and no HDAC-inhibitor combination has become standard in a solid tumour.

Key Takeaways

• ·HDAC inhibitors raise protein acetylation broadly, affecting histones and many non-histone targets.
• ·They are approved mainly for T-cell lymphomas and, in combination, for multiple myeloma.
• ·Solid-tumour activity has been disappointing and there is no established predictive biomarker.