Abstract 361: Identification of a novel dependence on the SWI/SNF chromatin remodeling complex in uveal melanoma

Uveal melanoma is a rare and aggressive cancer that originates in the pigmented tissues of the eye, which include the iris, the choroid and the ciliary body. To date, no targeted therapies have been approved for this cancer, and much remains to be described about the underlying biology of the disease. The most common driver mutation is an activating mutation in either the GNAQ or GNA11 GTPase, which in turns leads to hyperactivation of the MAPK pathway, but the precise downstream effectors driving tumorigenesis are poorly understood. Using pooled shRNA screening, we discovered that the SWI/SNF complex represents a novel genetic vulnerability in uveal melanoma, and further interrogated this dependency by a more targeted analysis across various uveal melanoma cell lines. While we observed the dropout of multiple SWI/SNF complex subunits in the screens, we defined the ATPase activity of SWI/SNF as central to the observed phenotype, implicating the chromatin remodeling function of the SWI/SNF complex in this phenotype. The regulation of gene expression by transcription factors can involve coordinated activity of SWI/SNF directed chromatin remodeling activity, so we began to investigate mechanistic links between SWI/SNF and other transcription factors such as MITF, which is known to play important roles in the differentiation of melanocytes. We observed that depletion of SWI/SNF affected transcription of certain MITF target genes, and are further investigating the precise pathways that are altered with SWI/SNF modulation. Taken together, these data suggest that the SWI/SNF complex plays an important role in maintaining tumor cell survival in uveal melanoma, and may represent a novel therapeutic target. Citation Format: Florencia Rago, Xiaoqin Xiang, Aurore Desplat, Emilie Niemezyk, David Ruddy, Grainne Kerr, Eusebio Manchado Robles, Deborah Castelletti, Zainab Jagani. Identification of a novel dependence on the SWI/SNF chromatin remodeling complex in 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 361.