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

Chory, Emma J.; Kirkland, Jacob G.; Chang, Chen‐Ming; D'Andrea, Vincent; Gourisankar, Sai; Dykhuizen, Emily C.; Crabtree, Gerald R.

doi:10.1021/acschembio.0c00312

Cited by 21 publications

(12 citation statements)

References 60 publications

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“…Vulnerability towards inhibition of the regulatory ATPases of mSWI/SNF complexes has been described in other cancer types and the development of small molecules directed against BRG1 and BRM has been promoted in recent years 17,18,70 . Given our observation that SMARCA4-containing BAF complexes seem to be most important to repress myogenic differentiation in FP-RMS, the avenue to selectively inhibit ARID1A containing assemblies 71 deserves attention in future studies.…”

Section: Discussionmentioning

confidence: 99%

BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

Laubscher

Gryder²,

Sunkel

et al. 2021

Preprint

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Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state wile blocking terminal differentiation. Here we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define, for the first time, the mSWI/SNF repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes act as sensors of chromatin state and are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes which is reproduced by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

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Section: Discussionmentioning

confidence: 99%

BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

Laubscher

Gryder²,

Sunkel

et al. 2021

Preprint

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“…However, a non-toxic 12-membered macrolactam, BRD-K98645985, was recently identified in a high-throughput screen for inhibitors of BAF-mediated transcription in cells, which seems to preferentially bind to ARID1A-containing BAF complexes and relieves transcriptional repression of HIV-I [ 96 ]. This compound was further found to synergize with ATR (ataxia-telangiectasia mutated (ATM) and Rad3-related protein kinase) inhibitor VE-821 and induce a synthetic lethal interaction in cancer cells [ 97 ], which had been described before in RNA interference screens [ 98 ]. The binding site or the specific target protein of BRD-K98645985 remains elusive.…”

Section: Direct Targeting Of Swi/snf Components For Inducing Synthetic Lethalitymentioning

confidence: 99%

Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy

et al. 2021

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Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20–25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.

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“…In addition to PBRM1, BRD7 and BRD9 were also identified as potential therapeutic markers to predict synthetic lethality under the treatment with chemotherapeutic drugs and PARP inhibitors [ 197 , 198 ]. Furthermore, the DNA damage repair-associated inhibitors ATR/ATM in combination with ARID1A-deficiency or BAF complex -inhibition functionally synergize, suggesting a potential synthetic lethal strategy to target tumor cells [ 199 , 200 ]. Together, these studies provide important indications of the synergy between chromatin remodeler inhibitors and DNA damage repair-associated inhibitors, especially in combination with chemotherapeutic agents.…”

Section: Targets For Cancer Therapymentioning

confidence: 99%

Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy

Zhang

2022

IJMS

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ATP-dependent chromatin-remodeling complexes can reorganize and remodel chromatin and thereby act as important regulator in various cellular processes. Based on considerable studies over the past two decades, it has been confirmed that the abnormal function of chromatin remodeling plays a pivotal role in genome reprogramming for oncogenesis in cancer development and/or resistance to cancer therapy. Recently, exciting progress has been made in the identification of genetic alteration in the genes encoding the chromatin-remodeling complexes associated with tumorigenesis, as well as in our understanding of chromatin-remodeling mechanisms in cancer biology. Here, we present preclinical evidence explaining the signaling mechanisms involving the chromatin-remodeling misregulation-induced cancer cellular processes, including DNA damage signaling, metastasis, angiogenesis, immune signaling, etc. However, even though the cumulative evidence in this field provides promising emerging molecules for therapeutic explorations in cancer, more research is needed to assess the clinical roles of these genetic cancer targets.

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

Cited by 21 publications

References 60 publications

BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy

Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy

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