Therapeutic Targeting of BET proteins in Sarcoma.

Abstract

Bromodomain and extraterminal domain (BET) 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 treatment of sarcomas, for they block interaction of BETs with acetylated lysines, modify gene expression, and create an imbalance in transcription and replication kinetics. BETi also disrupt transcriptional programs driven by oncogenic fusion proteins found in some sarcomas. Preclinical studies demonstrate efficacy of BETi in inducing apoptosis, disrupting DDR, and reducing tumor growth, either as monotherapy or in combination with chemotherapy or other targeted agents, such as PI3K, HDAC, 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, selectivity, and exploring combination therapies, such as BETi with DDR inhibitors. This review summarizes the preclinical studies on BET inhibition and discusses clinical trial activity, providing insight into the potential of BETi in sarcoma therapy.