Evaluation of HDAC8 as a Druggable Target in STAG2-Mutant Ewing Sarcoma.

Ewing sarcoma is an aggressive pediatric cancer for which no targeted therapies have been approved. This disease is driven by EWSR1::ETS family fusions that, like most fusion transcription factors, have proven difficult to target directly. Here, we focus on identifying actionable dependencies within the high-risk STAG2-mutant (STAG2-mut) disease subtype of Ewing sarcoma. In STAG2-mut Ewing sarcoma, STAG1 knockout is synthetically lethal but is not readily druggable. Using the Cancer Dependency Map (DepMap), we identify histone deacetylase 8 (HDAC8) as an enriched vulnerability in this molecular context. CRISPR validation and a newly developed HDAC8 degrader, XY-09-36, confirm this selective dependency and suggest increased reliance on HDAC8-mediated cohesin regulation when STAG2 is lost. These findings establish HDAC8 as a context-dependent, pharmacologically accessible vulnerability and outline a framework for discovering rational targets in tumor subtypes where primary drivers are intrinsically hard to drug.