Pluto Bioinformatics

GSE124059: Inhibition of NF-B-dependent signaling enhances sensitivity and overcomes resistance to BET inhibition in uveal melanoma

Bulk RNA sequencing

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. SOURCE: Benjamin Tycko ( - HUMC

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