The discovery of SWI/SNF chromatin remodeling activity as a novel and targetable dependency in uveal melanoma

Uveal melanoma is a rare and aggressive cancer that originates in the uveal tissue of the eye. Currently, there are no approved targeted therapies for this cancer, and very few effective treatments are available. While activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, other targetable molecular players are only partially understood. Through new analysis of unbiased, functional genomics screens and comprehensive validation studies in a panel of uveal melanoma cell lines, we find evidence that the SWI/SNF complex is essential in uveal melanoma. The mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) are often mutated in cancers and described as tumor suppressors, yet context specific roles for these complexes in the maintenance of certain cancers are beginning to emerge. We determined that the catalytic activity of SWI/SNF is critical, and further translated these findings with our recently described small molecule inhibitors of BRM and BRG1, the closely related catalytic subunits of the SWI/SNF complexes. Finally, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage specific transcription factor MITF, suggesting that SWI/SNF cooperates with MITF to drive a lineage specific 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 to the treatment of this cancer.

葡萄膜黑色素瘤（Uveal Melanoma）是一种罕见且侵袭性极强的癌症，起源于眼部的葡萄膜组织。目前尚无针对该癌症的获批靶向治疗方案，可用的有效治疗手段亦极为有限。尽管G蛋白α亚基GNAQ与GNA11的激活性突变是该病的关键遗传驱动因素，但其他可靶向的分子靶点仍未被充分阐明。本研究通过对无偏倚功能基因组筛选的全新分析，以及针对一组葡萄膜黑色素瘤细胞系的全面验证实验，证实SWI/SNF复合体（SWI/SNF Complex）在葡萄膜黑色素瘤中发挥必需作用。哺乳动物SWI/SNF染色质重塑复合体（又称BAF/PBAF）常在癌症中发生突变，既往被归类为肿瘤抑制因子，但这类复合体在特定癌症维持中的上下文特异性功能正逐渐被揭示。我们明确了SWI/SNF的催化活性至关重要，并结合本团队近期报道的SWI/SNF复合体高度同源催化亚基BRM与BRG1的小分子抑制剂，将上述发现实现了转化应用。本研究还阐明了SWI/SNF复合体与黑色素细胞谱系特异性转录因子MITF（小眼畸形相关转录因子）之间的功能关联，提示SWI/SNF可与MITF协同驱动一套谱系特异性转录程序，该程序对葡萄膜黑色素瘤细胞的存活不可或缺。上述研究凸显了SWI/SNF复合体在葡萄膜黑色素瘤中的关键作用，并为该癌症的治疗提供了全新途径。