BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors

Wang, Xiaofeng; Wang, Su; Troisi, Emma C.; Howard, Thomas P.; Haswell, Jeffrey R.; Wolf, Bennett; Hawk, William H.; Ramos, Pilar; Oberlick, Elaine; Tzvetkov, Evgeni P.; Ross, Aaron; Vázquez, Francisca; Hahn, William C.; Park, Peter J.; Roberts, Charles W.M.

doi:10.1038/s41467-019-09891-7

Cited by 152 publications

(195 citation statements)

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“…This suggests that the BAF complex containing the SS18‐SSX fusion protein is deficient in SMARCB1 function. SMARCB1‐deficient cancer cells and SS18‐SSX fusion cancer cells are synthetic lethal because of inhibition of a subunit of the ncBAF complex, such as BRD9 . Thus, BAF complex‐deficient cancers, such as SMARCB1‐deficient cancers, depend on the function of the residual ncBAF complex.…”

Section: Synthetic Lethal Targets Based On Targeting the Interaction mentioning

confidence: 99%

“…are synthetic lethal because of inhibition of a subunit of the ncBAF complex, such as BRD9. 18,29,30 Thus, BAF complex-deficient cancers, such as SMARCB1-deficient cancers, depend on the function of the residual ncBAF complex. A BRD9 inhibitor would therefore be a promising strategy for SMARCB1-deficient cancers.…”

Section: Smarcb1-deficient Cancer Cells and Ss18-ssx Fusion Cancer Cellsmentioning

confidence: 99%

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Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Sasaki

Ogiwara

2020

Cancer Science

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The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss‐of‐function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex.

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Section: Synthetic Lethal Targets Based On Targeting the Interaction mentioning

confidence: 99%

Section: Smarcb1-deficient Cancer Cells and Ss18-ssx Fusion Cancer Cellsmentioning

confidence: 99%

Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Sasaki

Ogiwara

2020

Cancer Science

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“…The Cancer Dependency Map project (DepMap) is an ongoing project to identify essential genes across hundreds of cancer cell lines using genome-wide CRISPR and shRNA screens (Tsherniak et al, 2017;Behan et al, 2019). It has already been used successfully to discover genetic vulnerabilities of cancer cells (Sandoval et al, 2018;Wang et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

A tool for browsing the Cancer Dependency Map reveals functional connections between genes and helps predict the efficacy and selectivity of candidate cancer drugs

Shimada

Mitchison

2019

Preprint

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Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover gene dependency in hundreds of cancer cell lines. DepMap is a powerful drug discovery tool, but can be challenging to use without professional bioinformatics assistance. We combined CRISPR and shRNA screening data from DepMap and built a non-programmer-friendly browser (https://labsyspharm.shinyapps.io/depmap) that reports, for each gene, the growth reduction that can be expected on loss of a gene or inhibition of its action (efficacy) and the selectivity of this effect across cell lines. Cluster analysis revealed proteins that work together in pathways or complexes. This tool can be used to 1) predict the efficacy and selectivity of candidate drugs; 2) identify targets for highly selective drugs; 3) identify maximally sensitive cell lines for testing a drug; 4) target hop, i.e., navigate from an undruggable protein with the desired selectively profile, such as an activated oncogene, to more druggable targets with a similar profile; and 5) identify novel pathways needed for cancer cell growth and survival. Keywords (up to 10):Cancer Dependency Map, precision medicine, essential genes, CRISPR, RNAi, synthetic lethality, ECHODOTS, cluster analysis, web tool, shiny to run the tool locally, but it will not be updated. In the following, the analysis workflow is explained ( Fig. 1B). Efficacy-Selectivity (All genes)This service allows a user to explore efficacy and selectivity. The output is split into two panels. On the left, a scatterplot displaying efficacy and selectivity of all the genes is always shown (3, the number corresponds in Fig. 1B-C). By hovering over the points on the plot with the cursor, one can identify specific genes. When a partial or full gene name is provided in a text box in the input sidebar (1), genes that are partially matched to the query as well as their efficacy and selectivity are listed on the right panel, when the "Gene list" tab is selected (4). One of the listed genes is highlighted in pink.The points on the scatter plot corresponding to the listed genes are shown in orange with the highlighted gene on the list in red. When switching to the "Lineage" tab, perturbation scores of the highlighted gene in individual cell lines are shown, stratified by lineages (5). To view the scores of other genes on the Gene list, the user selects a different gene from the drop-down menu in the Input sidebar (2).Functional clusters (essential genes only) 2,492 genes were found essential in our analysis. We clustered perturbation profiles of the genes, as described in detail below. The output consists of three panels. On top left is the same essentiality vs selectivity plot of the essential genes (9). The bottom left plot shows the similarity of perturbation score profiles across genes (10). Adjacent points in the plot are expected to be functionally connected. When one essential gene is chosen from the top left drop-down menu (6), the cluster containing the query ge...

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“…These complexes are combinatorially assembled from 16 subunits encoded by 31 genes (Figure 1A) giving them specific roles in many biologic processes. Recently, BAF complexes have been found to take on non-canonical assemblies (ncBAF) 10,11,58 , which are essential in malignant rhabdoid tumors 10 and synovial sarcoma 11 ( Figure 1A). Although many of the subunits are required for essential cellular mechanisms 12,13 , other subunits have highly selective functions [14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a BRG1 ATPase inhibitor was discovered 22 , yet its non-specific inhibition of both BRG1 and BRM would likely be toxic in patients due to the essential nature of the core ATPase subunits in cellular viability in many cell types. 10 As members of the thrithorax group proteins, mSWI/SNF complexes are generally thought to be activators of transcription. However, they can also directly inhibit expression of PRC1 genes in murine embryonic stem cells 23 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing

Chory

Kirkland

Chang

et al. 2019

Preprint

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SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively non-toxic and importantly synergize with ATR inhibitors in killing cancer cells. Our studies suggest an avenue for therapeutic enhancement of ATR/ATM inhibition and provide evidence for chemical synthetic lethality of BAF complexes as a therapeutic strategy in cancer. Figure 1: Strategy for assessing hyper-synthetic lethality of combination BD98 and ATRi (A) Macromolecular assembly of SWI/SNF complexes. BAF/PBAF-specific subunits labelled in blue/red respectively. (B) Workflow of screen used to identify putative BAF inhibitors. (C) Structure of BD98. (D) Summary of results (combination index scores, normalized isobolograms) obtained in Chou-Talalay method for assessment of synergy

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BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors

Cited by 152 publications

References 35 publications

Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

A tool for browsing the Cancer Dependency Map reveals functional connections between genes and helps predict the efficacy and selectivity of candidate cancer drugs

Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing

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