Abstract B29: Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations

Uveal melanoma (UM) represents the most common intraocular malignancy, and there are no effective treatments for this aggressive disease. Nearly 80% of UM is characterized by oncogenic mutations in G protein subunits Gnaq and Gna11, and 70% have extra copies of the oncogene MYC. Chromatin regulators have become attractive targets for cancer therapy. In particular, the BET-bromodomain inhibitor JQ1 has shown selective inhibition of c-Myc expression, followed by the suppression of c-Myc-dependent target genes. Treatments of UM cell lines with JQ1 showed that the Gnaq/Gna11 mutant cells were the most sensitive to BET inhibition with induction of cell death, while the cells without the mutations underwent cell cycle arrest in G1. Microarray analysis of UM cells revealed that several genes were differentially regulated by JQ1 treatment in Gnaq/11 mutant cells, with the downregulation of c-Myc, of the anti-apoptotic protein Bcl-2, and DNA repair proteins Rad51 and Brca1. While depletion of each of these genes did not affect cell viability, the concomitant silencing of Rad51 and Bcl-2 represented the minimal requirement to mimic the apoptotic effects of JQ1. As opposed to hematopoietic cancer cell lines, c-Myc depletion did not seem to play a major role in inhibiting the growth of these cells. Furthermore, the treatment with JQ1 resulted in significant antitumor activity in a mouse xenograft model of uveal melanoma with Gnaq mutation. Our results suggest the potential therapeutic use of BET bromodomain inhibitors for treating uveal melanoma with Gnaq/Gna11 mutations. Citation Format: Grazia Ambrosini. Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B29.