Uveal melanoma (UM) is an aggressive intraocular malignancy with high tendency to metastasize to the liver. Currently available drugs have shown limited clinical activity in patients with UM and there is an urgent need for new effective therapies. Recent findings from our laboratory demonstrated that UM cells are sensitive to BET inhibitors (BETi) through the induction of cell cycle arrest and apoptosis. However, despite the initial inhibitory effects, UM cells acquire resistance to this class of drugs following chronic drug exposure. In order to understand the mechanistic basis for BETi resistance in UM, we assessed genome-wide CpG methylation patterns in UM cell lines that had been rendered resistant to the clinical BET inhibitor PLX51107 (Plexxikon, Berkeley, CA) following chronic drug exposure. The comparison between BET inhibitor-resistant versus sensitive cell lines revealed differential methylation of 1700 genes, including several involved in Wnt/β-catenin signaling, as well as other signaling pathways. Immunoblotting analysis confirmed that β-catenin protein was induced and activated in the resistant cells, while depletion of β-catenin by siRNA re-sensitized the resistant cells to the BET inhibitor. We then explored several combinations of PLX51107 with drugs that block β-catenin transcriptional activity through inhibition of its phosphorylation by PAK4 or through the inhibition of binding partners like Cdk8 and CBP. All these combinations increased the activity of the BET inhibitor in both sensitive and resistant cells, and these effects were synergistic, with combination indexes (CI) <1. These observations support the evidence that acquired resistant to BET inhibitors is mediated, at least in part, by activation of the Wnt/β-catenin pathway, and inhibitors of this pathway may provide a means to overcome acquired BET inhibitor resistance in UM patients treated with this class of drugs.
Citation Format: Grazia Ambrosini, Benjamin Tycko, Chaterine Do, Gary K. Schwartz. Resistance to BET inhibitors involves the β-catenin pathway in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4154. doi:10.1158/1538-7445.AM2017-4154