Cyril Roussel-Simonin, Aranzazu Fernandez-Martinez, Sophie Postel‐Vinay, Fernanda Mosele, A.A. Viansone, Christophe Massard, Adrien Mouren, Julien Vibert, Barbara Pistilli
Breast cancer is a leading cause of cancer-related mortality among women, with hormone receptor-positive (HR + ) disease representing the majority of cases. Despite advances in targeted therapies and antibody-drug conjugates, resistance to treatment remains a significant challenge, necessitating innovative therapeutic strategies. Epigenetic dysregulation, particularly involving histone acetylation, plays a crucial role in tumorigenesis and therapy resistance. Lysine acetyltransferase 6 (KAT6A/B), key regulators of chromatin structure and gene expression, have emerged as promising therapeutic targets in HR+ breast cancer. This review highlights the molecular mechanisms by which KAT6A/B modulate histone acetylation and gene regulation, emphasizing their roles in oncogenic pathways and cellular processes such as transcriptional activation, chromatin remodeling, and regulation of cellular senescence. We discuss preclinical evidence supporting the therapeutic potential of KAT6 inhibition and the challenges faced in epigenetic drug development, including the need for robust biomarker-driven approaches. Finally, we explore the prospects for integrating KAT6 inhibitors with existing therapies to overcome resistance and improve patient outcomes in breast cancer.