Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles for the mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) in various cancer lineages. Here, we find evidence that the SWI/SNF complex is essential through analysis of functional genomics screens and further validation in a panel of uveal melanoma cell lines using both genetic tools and small-molecule inhibitors of SWI/SNF. In addition, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage–specific transcription factor Microphthalmia-associated Transcription Factor, suggesting that these two factors cooperate to drive a transcriptional program essential for uveal melanoma cell survival. These studies highlight a critical role for SWI/SNF in uveal melanoma, and demonstrate a novel path toward the treatment of this cancer.

中文翻译：

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发现 SWI/SNF 染色质重塑活动是葡萄膜黑色素瘤的一种新的和可靶向的依赖性

葡萄膜黑色素瘤是一种罕见的侵袭性癌症，起源于眼部。目前，没有批准的靶向疗法，也很少有针对这种癌症的有效疗法。尽管 G 蛋白 α 亚基 GNAQ 和 GNA11 中的激活突变是该疾病的关键遗传驱动因素，但已确定的其他药物靶点很少。最近，研究已经确定了哺乳动物 SWI/SNF 染色质重塑复合物（也称为 BAF/PBAF）在各种癌症谱系中的特定背景作用。在这里，我们通过分析功能基因组筛选和使用遗传工具和 SWI/SNF 小分子抑制剂在一组葡萄膜黑色素瘤细胞系中进一步验证，发现证据表明 SWI/SNF 复合物是必不可少的。此外，我们描述了 SWI/SNF 复合物与黑素细胞谱系特异性转录因子小眼相关转录因子之间的功能关系，表明这两个因子协同驱动对葡萄膜黑色素瘤细胞存活至关重要的转录程序。这些研究强调了 SWI/SNF 在葡萄膜黑色素瘤中的关键作用，并展示了治疗这种癌症的新途径。