Inhibition of bromodomain and extra-terminal motif (BET) proteins in pediatric sarcoma: A systematic review of in vitro and in vivo studies.

BET inhibitors (BETi), especially those targeting BRD4, show promising preclinical activity against pediatric sarcomas by disrupting oncogenic transcription. This systematic review of 26 studies highlights the anti-proliferative and pro-apoptotic effects of BETi across five pediatric sarcoma types. In vivo data show a decrease in tumor growth, with better results when combined with other therapies. This systematic review revealed that, whereas early investigations mostly rely on pan-BETi, recent studies focus on newer and more specific agents. Accordingly, we reported that ABBV-744 and RVX-208, which selectively target the BD2 domain, and GNE-987, a specific BRD4 degrader, are the most promising inhibitors. However, ABBV-075, a pan-BETi, also exhibits high efficacy, being effective at low doses. Nevertheless, translating these experimental findings into clinical practice remains difficult because of resistance, toxicity, and inconsistent responses. Future approaches include using biomarkers for patient selection, developing isoform-specific BETi, and designing rational combination therapies to enhance treatment for these aggressive pediatric cancers.