Identification of targetable epigenetic vulnerabilities for uveal melanoma

Uveal melanoma (UM) is the most common adult primary intraocular malignancy, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM remains highly resistant to therapy and is almost invariably fatal. The strongest genetic driver of UM metastasis is loss of function of the tumor suppressor BRCA-associated protein 1 (BAP1), which leads to widespread epigenetic dysregulation. To identify novel therapeutic strategies, we investigated whether targeting the epigenome could reveal new vulnerabilities in UM. We performed high-throughput compound screening using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. While previous clinical trials with BET inhibitors for UM treatment have failed clinically, we found substantial heterogeneity in the efficacy of different BET inhibitors in UM. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and prevented detectable metastases in the bones, spinal cord, and brain. Transcriptomic analysis revealed a strong overlap between BET inhibition and histone deacetylase (HDAC) inhibition-- an approach currently under clinical evaluation for UM treatment. BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuron-like phenotype in UM cells. These findings establish BET inhibition as a potent and previously underappreciated vulnerability for metastatic UM.