Targeting BRD4 in cancer therapy: From inhibitors and degraders to novel combination strategies and resistance mechanisms.

Bromodomain-containing protein 4 (BRD4), a key member of the BET family, is integral to epigenetic regulation through its recognition of acetylated histones and its modulation of transcriptional programs associated with cell cycle progression, DNA damage repair, and inflammatory responses. The overexpression of BRD4 has been linked to a diverse array of malignancies, including basal-like breast cancer, melanoma, and epithelial ovarian cancer, thereby establishing it as a promising therapeutic target. In the past year, significant advancements have been made in the development of novel agents targeting BRD4, particularly selective inhibitors and proteolysis-targeting chimeras (PROTACs), which demonstrate enhanced efficacy and specificity. This review provides a comprehensive summary of the functions and underlying mechanisms of BRD4 in oncogenesis. It further highlights the recent progress in the development of BRD4-directed inhibitors and degraders in the past year. Additionally, the review discusses emerging mechanisms of resistance to BRD4-targeted therapies and explores rational combination strategies to mitigate such resistance. The objective of this overview is to offer timely and insightful information that may facilitate the advancement of more effective epigenetic therapies targeting BRD4-dependent cancers.