4.8 Article

Inhibition of NF-κB-Dependent Signaling Enhances Sensitivity and Overcomes Resistance to BET Inhibition in Uveal Melanoma

Journal

CANCER RESEARCH
Volume 79, Issue 9, Pages 2415-2425

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-3177

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Funding

  1. Melanoma Research Alliance (MRA) [402803]
  2. NIH [R01 160495]
  3. Plexxikon Inc. [PLX51107]

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Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here, we evaluated the mechanisms of BETi resistance in uveal melanoma, 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. NF-kappa B inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment. Furthermore, genes involved in NF-kappa B 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-kappa B signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma. Significance: These findings provide evidence that inhibitors of NF-kappa B signaling synergize with BET inhibition in in vitro and in vivo models, suggesting a clinical utility of these targeted therapies in patients with uveal melanoma.

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