Abstract 1410: Gnaq/11 mutant uveal melanoma is susceptible to Brd4 inhibition by JQ1

Abstract

Abstract Uveal melanoma (UM) represents the most common intraocular malignancy in the United States, and there are no effective treatments for this aggressive disease. Uveal melanoma is characterized by oncogenic mutations in Gnaq and Gna11, which activate the mitogen-activated protein kinase pathway (MAPK). Furthermore, both primary and metastatic UM are characterized by genetic abnormalities, including the amplification of the chromosomal arm 8q and monosomy of chromosome 3, which are significantly associated with poor prognosis. The oncogene MYC, which is located on 8q24.1, is amplified in nearly 70% of uveal melanoma, and is also regulated by the MAPK pathway. 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. We examined the effects of JQ1 in a panel of 8 UM cell lines, including cell lines with Gnaq/Gna11 mutations (92.1, Omm1.3, Mel270, Mel202, Omm1), a cell line with MYC amplification (Mel290), and cells without either mutation or amplification (C918, Mel285). The Gnaq/Gna11 mutant cells were the most sensitive to growth inhibition at nanomolar concentrations of JQ1 (IC50=200nM), followed by the cell line with amplified MYC (IC50=1μM), while the cells without mutation or amplification exhibited little inhibition. We also examined the biochemical effects of JQ1 treatment, which caused a dose- and time-dependent suppression of c-Myc as well as survivin, XIAP, ERK1 and E2F1, while p21and the pro-apoptotic protein Bim were induced in all the cell lines. Interestingly, JQ1 also suppressed the anti-apoptotic protein Bcl-xL and induced PARP cleavage only in the Gnaq/Gna11 mutant cells. Flow cytometric analysis indicated a cell cycle arrest in G1 in all the cell lines and an apoptotic population in sub-G1in the mutant cells. Furthermore, treatment with JQ1 resulted in significant antitumor activity in mouse xenograft models of uveal melanoma with Gnaq mutation. All together, these observations support the evidence that JQ1 represent a promising therapeutic approach for uveal melanoma with Gnaq/Gna11 mutations. Citation Format: Grazia Ambrosini, Gary K. Schwartz. Gnaq/11 mutant uveal melanoma is susceptible to Brd4 inhibition by JQ1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1410. doi:10.1158/1538-7445.AM2014-1410