Inhibition of NF-κB-dependent signaling enhances sensitivity and overcomes resistance to BET inhibition in uveal melanoma

ABSTRACT: Bromodomain and extra terminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early success of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. We evaluated the mechanisms of BETi resistance in uveal melanoma (UM), a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107, and RNA sequencing of BETi-resistant cells. We found that the NF-kB inhibitors synergistically sensitized UM cells to PLX51107 treatment. Furthermore, genes involved in NF-kB signaling were upregulated in BETi-resistant cells and the transcription factor CEBPD contributed to the mechanism of resistance. These findings suggest that inhibitors of NF-kB signaling may improve the efficacy of BET inhibition in patients with advanced UM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124059 | GEO | 2019/03/18

REPOSITORIES: GEO