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

Rago, Florencia and Elliott, Ginell and Li, Ailing and Sprouffske, Kathleen and Kerr, Grainne and Desplat, Aurore and Abramowski, Dorothee and Golji, Javad and Farsidjani, Alireza and Xiang, Xiaoqin and Bushold, Geoffrey and Chung, Franklin and Feng, Yun and Shirley, Matt and Bric, Anka and Vattay, Anthony and Moebitz, Henrik and Nakajima, Katsumasa and Adair, Chris and Mathieu, Simon and Ntaganda, Rukundo and Smith, Troy and Papillon, Julien and Kauffmann, Audrey and Ruddy, David and Bhang, Hyo-eun and Castelletti, Deborah and Jagani, Zainab (2020) The discovery of SWI/SNF chromatin remodeling activity as a novel and targetable dependency in uveal melanoma. Molecular cancer therapeutics. ISSN 1538-8514

Abstract

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.

Item Type: Article
Date Deposited: 18 Aug 2020 00:45
Last Modified: 18 Aug 2020 00:45
URI: https://oak.novartis.com/id/eprint/42569

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