78 Quick summary: Scientists at Baylor College of Medicine have challenged the traditional understanding of how histone deacetylase inhibitors function, discovering that these critical cancer drugs retain their therapeutic benefits even when their ability to block the target enzymes is entirely removed. The research indicates that the anti cancer compounds successfully interfere with additional unidentified protein pathways, which helps explain the highly variable patient responses frequently observed in solid tumour clinical settings. This breakthrough has profound implications for public policy and healthcare practice, offering a clear roadmap for drug developers to design next generation treatments with greater precision, accelerate the discovery of predictive biomarkers, and ultimately improve survival outcomes and emotional well-being for oncology patients. Researchers at Baylor College of Medicine and collaborating institutions are challenging the traditional understanding of how cancer drugs known as histone deacetylase (HDAC) inhibitors function. For decades, scientists believed these drugs worked by blocking HDAC enzymes, which drive cancer development by altering how genes are turned on and off. The new study, published in Signal Transduction and Targeted Therapy, suggests the drugs may also affect other pathways beyond HDAC inhibition. “The DNA inside cells is wrapped around proteins called histones. Chemical changes to histones, such as adding or removing acetyl groups, are believed to determine which genes are active,” said corresponding author Dr Zheng Sun, associate professor of medicine in endocrinology, diabetes, and metabolism, and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. HDACs remove acetyl groups from histones. The prevailing idea has been that increasing histone acetylation with HDAC inhibitors promotes beneficial gene expression changes that may slow cancer or lead to cancer cell death. “Yet, some findings do not support this idea,” Sun said. “In some contexts, HDACs do not promote cancer, but act as tumour suppressors instead. Sometimes HDAC inhibitors can increase histone acetylation but with only moderate effects on gene expression.” Sun and his colleagues applied multiple unbiased approaches to investigate the relationship between HDACs and various cancer types, and the role of HDACs in the anti-cancer activity of these inhibitors. They conducted these studies in multiple solid tumour models in which HDAC inhibitors are being tested clinically. “Our unbiased bioinformatics analyses showed that HDACs are not always associated with cancer growth — different types of HDACs or their levels do not correlate consistently with most cancers or patient survival,” said first author Dr Chaitra Rai, postdoctoral fellow in the Sun lab. “We also found that the anti-cancer effects of the HDAC inhibitor FK228 were independent of its ability to inhibit HDACs in a mouse model. With HDAC inhibitors that block a family of HDACs, we eliminated their ability to inhibit the enzymes, yet the inhibitors retained most of their anti-cancer effects in a mouse model.” Although some HDAC inhibitors may act through HDACs in certain contexts, the results suggest this mechanism is not as universal as previously assumed. HDAC inhibitors are already approved for treating certain blood cancers and are under investigation in hundreds of clinical trials for solid tumours and other conditions. “We propose that HDAC inhibitors may also interfere with other proteins and that targeting such proteins may suppress cancer,” Sun said. “Identifying other molecular targets of HDAC inhibitors represents an important step toward improving cancer treatment.” The findings could influence future drug design and combination therapies. Rather than focusing exclusively on enhancing histone acetylation, researchers may now explore additional pathways that contribute to the therapeutic benefits of these compounds. This shift could help explain variable patient responses seen in clinical settings and guide the development of next-generation inhibitors with improved specificity. As clinical trials for HDAC inhibitors in solid tumours continue, the study’s authors emphasise the need for mechanistic clarity. Better understanding could accelerate the identification of biomarkers that predict which patients are most likely to benefit, supporting more personalised approaches to cancer care.