Abstract 5852: FGF2 confers resistance to novel BET inhibitors in metastatic uveal melanoma

Abstract

Abstract Uveal melanoma (UM) is the most common intraocular malignancy in adults and frequently metastasizes to the liver. Metastatic UM responds poorly to chemotherapy, immunotherapy and MAPK pathway inhibitors; hence, there is an urgent unmet need for new treatment strategies. UM has a low mutational burden and progression is associated with abberrant transcriptional programs. Inhibition of epigenetic modulators involved in transcriptional regulation such as the bromodomain and extraterminal domain (BET) proteins, may be feasible for the treatment of UM. Pre-clinically, JQ1, a first generation BET inhibitor, has been shown to suppress UM growth. Additionally, a multi-site clinical trial is ongoing testing a novel BET inhibitor, PLX51107 (Plexxikon Inc) in metastatic UM patients. Since growth factors in the tumor microenvironment potentially contribute to intrinsic resistance and poor responses to therapies, we determined effects of growth factors on the efficacy of BET inhibitors in metastatic UM cells. We show that FGF2 provides resistance of UM cells to the growth inhibitory effects of BET inhibitors, JQ1, PLX51107 and the third generation inhibitor, PLX72853. FGF2 rescued BET inhibitor-induced apoptosis and cell cycle arrest, which was associated with reversal of the decreased expression of cell cycle regulators (cyclin D1, phospho-RB) and increased expression of pro-apoptotic markers (cleaved PARP, Bim). Importantly, FGF receptor (FGFR) inhibitors reversed FGF2-induced BET inhibitor resistance. As UM predominantly metastasizes to the liver, we investigated FGF2 production by hepatic stellate cells. We show that hepatic stellate cells secrete FGF2 and stellate cell conditioned medium protects metastatic UM cells against the growth inhibitory effects of BET inhibitors. Interestingly, BET inhibitor treatment of UM cells elevated FGFR protein expression and this finding is also shown in UM cell xenograft tumors and in patient tumor samples following PLX51107 treatment. These results indicate that the FGF2/FGFR pathway is activated to promote resistance to BET inhibition via the secretion of FGF2 in the tumor stroma and adaptive upregulation of FGFR expression in UM. In conclusion, our studies suggest that co-targeting of FGFR signaling and BET proteins may be required to maximize the responses of metastatic UM to BET inhibitors. Citation Format: Vivian Chua, Timothy Purwin, Connie Liao, Andrew Aplin. FGF2 confers resistance to novel BET inhibitors in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5852.