73 A recent study published in Nature Cancer reveals significant strides in the pharmacological targeting of the cancer epigenome, highlighting new therapeutic strategies that hold promise for improving cancer treatment outcomes. Researchers Nathaniel W. Mabe, Jennifer A. Perry, Clare F. Malone, and Kimberly Stegmaier led the thorough review, which focuses on the mechanisms of epigenetic dysregulation in cancer and the creation of cutting-edge drugs that target these pathways. Epigenetic dysregulation is a hallmark of cancer, influencing disease initiation, maintenance, and therapy resistance. The study explores how epigenetic modifications, which alter gene expression without changing the DNA sequence, play a critical role in cancer progression. These modifications include DNA methylation, histone modification, and chromatin remodelling, all of which can lead to aberrant gene expression patterns that promote tumour growth and survival. The research underscores the therapeutic potential of targeting epigenetic proteins that regulate gene expression. Three classes of epigenetic inhibitors – DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and enhancer of zeste homolog 2 (EZH2) inhibitors—have already been approved by the U.S. Food and Drug Administration (FDA). These drugs represent a significant advancement in cancer treatment, especially for haematological malignancies. However, the study notes that the clinical efficacy of these drugs in solid tumours remains limited. The researchers highlight the need for selective targeting to minimise toxicity and enhance therapeutic benefits. For instance, while DNMT inhibitors are essential for both cancer and healthy cell survival, HDAC inhibitors could be selectively targeted due to redundancies among HDAC enzymes. This specificity could reduce off-target effects and improve patient outcomes. In addition to approved therapies, the study identifies several emerging epigenetic targets currently under preclinical investigation. These include histone ubiquitylase complex PRC1, chromatin reader ENL, and histone methyltransferase ASH1L. Targeting these proteins could offer new avenues for cancer therapy, particularly in cancers with specific genetic mutations or epigenetic dependencies. One promising target is the bromodomain and extraterminal (BET) protein family, which includes BRD2, BRD3, BRD4, and BRDT. BRD4, in particular, is a well-studied cancer target due to its role in regulating oncogenic gene expression. Inhibitors targeting BET proteins have shown efficacy in preclinical models and are currently being evaluated in clinical trials. By stopping the interaction between BET proteins and acetylated histones, these inhibitors stop oncogenes from being translated. The concept of synthetic lethality—where the inhibition of two genes results in cell death—has gained traction as a strategy for targeting cancer-specific vulnerabilities. The study discusses how targeting selective dependencies in cancer cells can enhance the therapeutic window of epigenetic inhibitors. For example, the loss of function in one epigenetic regulator could render cancer cells more dependent on another, creating an opportunity for targeted therapy. An example of this approach is the targeting of the cBAF (canonical BRG1/BRM-associated factor) and ncBAF (non-canonical BAF) complexes. Some types of cancer depend on the ncBAF complex subunit BRD9 because of changes in the SMARCB1 gene, which is a part of the cBAF complex. By targeting BRD9, researchers can exploit this synthetic lethality to selectively kill cancer cells while sparing healthy cells. The study provides a detailed overview of ongoing and completed clinical trials for various epigenetic drugs, highlighting the progress and challenges in this field. For instance, while the BET inhibitor pinometostat has shown proof-of-concept clinical remissions, its continuous 28-day infusion regimen poses practical challenges. Future drug development efforts are focused on improving the pharmacokinetic properties of these inhibitors to enhance their clinical utility. The researchers call for continued investigation into the epigenetic landscape of cancer to identify new therapeutic targets and improve existing treatments. They emphasise the importance of understanding the complex interplay between genetic and epigenetic factors in cancer in order to develop more effective and personalised therapies.