Therapeutic Targeting of BET Proteins in Sarcoma

Bromodomain and extraterminal (BET) domain protein family are epigenetic readers that regulate gene transcription, cell-cycle progression, and DNA damage response (DDR), making them attractive therapeutic targets for sarcomas, which are epigenetically dysregulated and genomically unstable. Sarcomas are molecularly heterogeneous with a high propensity for metastasis, resulting in poor clinical outcomes. BET inhibitors (BETi) hold promise for the treatment of sarcomas, for they block interaction of BETs with acetylated lysines, modify gene expression, and create an imbalance in transcription and replication kinetics. BETis also disrupt transcriptional programs driven by oncogenic fusion proteins found in some sarcomas. Preclinical studies demonstrate efficacy of BETis in inducing apoptosis, disrupting DDR, and reducing tumor growth, either as monotherapy or in combination with chemotherapy or other targeted agents, such as PI3K, histone deacetylases, and CHK1 inhibitors. Favorable results have been observed in clinical trials, but more studies are required to fully assess safety and efficacy as well as identify biomarkers of response and resistance. Ongoing research is focused on optimizing BETi safety and selectivity and exploring combination therapies, such as BETis with DDR inhibitors. This review summarizes the preclinical studies on BET inhibition and discusses clinical trial activity, providing insights into the potential of BETis in sarcoma therapy.