Mammalian SWI/SNF Chromatin Remodeling Complexes: Emerging Mechanisms and Therapeutic Strategies

Over 20% of human cancers carry a mutation in mSWI/SNF complex subunit genes.Mistargeting of mSWI/SNF activity by disease-relevant transcription factors contributes to oncogenic gene expression programs.Targetable synthetic lethal opportunities exist for cancers harboring perturbations in mSWI/SNF subunits.The presence of alternate mSWI/SNF complex subtypes and variants enables complex-specific pharmacological targeting.Discovery and development of novel, subunit-specific small-molecule inhibitors and degraders are ongoing. Small molecule-based targeting of chromatin regulatory factors has emerged as a promising therapeutic strategy in recent years. The development and ongoing clinical evaluation of novel agents targeting a range of chromatin regulatory processes, including DNA or histone modifiers, histone readers, and chromatin regulatory protein complexes, has inspired the field to identify and act upon the full compendium of therapeutic opportunities. Emerging studies highlight the frequent involvement of altered mammalian Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin-remodeling complexes (also called BAF complexes) in both human cancer and neurological disorders, suggesting new mechanisms and accompanying routes toward therapeutic intervention. Here, we review current approaches for direct targeting of mSWI/SNF complex structure and function and discuss settings in which aberrant mSWI/SNF biology is implicated in oncology and other diseases. Small molecule-based targeting of chromatin regulatory factors has emerged as a promising therapeutic strategy in recent years. The development and ongoing clinical evaluation of novel agents targeting a range of chromatin regulatory processes, including DNA or histone modifiers, histone readers, and chromatin regulatory protein complexes, has inspired the field to identify and act upon the full compendium of therapeutic opportunities. Emerging studies highlight the frequent involvement of altered mammalian Switch/Sucrose-Nonfermentable (mSWI/SNF) chromatin-remodeling complexes (also called BAF complexes) in both human cancer and neurological disorders, suggesting new mechanisms and accompanying routes toward therapeutic intervention. Here, we review current approaches for direct targeting of mSWI/SNF complex structure and function and discuss settings in which aberrant mSWI/SNF biology is implicated in oncology and other diseases. Gene regulation is crucial for the proper execution of all biological processes. The >3.2 billion base-pairs of DNA in every human cell are compacted into higher order chromatin structures, dynamic regulation of which is critical to ensure the proper timing, location, and sequence of events. A range of well-established processes govern chromatin topology, including DNA modifications, histone modifications, and ATP-dependent chromatin remodeling. In this review, we focus specifically on the mSWI/SNF (BAF) family of chromatin-remodeling complexes. Recent advances in proteomics, biochemical characterization strategies, genetic manipulation approaches, and 3D structural insights, have significantly advanced our understanding of the modular organization and assembly of the mSWI/SNF complexes. Notably, it is now clear that the products of the 29 genes encoding mSWI/SNF subunits assemble into three distinct mSWI/SNF complexes, termed canonical BAF (cBAF), polybromo-associated BAF (PBAF), and noncanonical BAF (ncBAF), each of which comprises common as well as complex-specific subunits (Figure 1A , Key Figure, and Table 1). All three complexes contain one of two mutually exclusive catalytic subunits, SMARCA4 or SMARCA2 (also referred to as BRG1 or BRM, respectively), which contain DNA-stimulated ATPase activity and utilize the energy provided by ATP hydrolysis to remodel chromatin through nucleosome sliding and eviction [1.Chiba H. et al.Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor.Nucleic Acids Res. 1994; 22: 1815-1820Crossref PubMed Scopus (274) Google Scholar, 2.Clapier C.R. et al.Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes.Nat. Rev. Mol. Cell Biol. 2017; 18: 407-422Crossref PubMed Scopus (248) Google Scholar, 3.Khavari P.A. et al.BRG1 contains a conserved domain of the SW'2 / SNF2 family necessary for normal mitotic growth and transcription.Nature. 1993; 366: 170-174Crossref PubMed Scopus (0) Google Scholar, 4.Kwon H. et al.Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex.Nature. 1994; 370: 477-481Crossref PubMed Scopus (608) Google Scholar, 5.Wang W. et al.Purification and biochemical heterogeneity of the mammalian SWI-SNF complex.EMBO J. 1996; 15: 5370-5382Crossref PubMed Scopus (626) Google Scholar]. The contribution of noncatalytic subunits to nucleosome remodeling remains to be comprehensively understood. Recently, SMARCB1 was shown to make direct contact with the nucleosome acidic patch; and this interaction is required for the full remodeling potential of the mSWI/SNF complex [6.Valencia A.M. et al.Recurrent SMARCB1 mutations reveal a nucleosome acidic patch interaction site that potentiates mSWI/SNF complex chromatin remodeling.Cell. 2019; 179: 1342-1356Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. The cBAF complex is a 12-member containing complex, distinguished by the incorporation of one of two mutually exclusive AT-rich interaction domain (ARID)-domain-containing proteins, ARID1A or ARID1B, as well as the tandem PHD domain-containing DPF2 subunit. The PBAF complex incorporates a distinct ARID protein, ARID2, in place of ARID1A/ARID1B, and also uniquely includes the bromodomain-containing subunits, PBRM1 and BRD7, and the PHD-containing subunit PHF10. Recently, a novel ncBAF complex was identified and characterized that does not incorporate an ARID or tandem-PHD PHF/DPF subunit, but instead uniquely contains the GLTSCR1/GLSTCR1L and BRD9 subunits [7.Alpsoy A. Dykhuizen E.C. Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes.J. Biol. Chem. 2018; 16: 3892-3903Abstract Full Text Full Text PDF Scopus (35) Google Scholar,8.Michel B.C. et al.A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation.Nat. Cell Biol. 2018; 20: 1410-1420Crossref PubMed Scopus (75) Google Scholar]. These distinct mSWI/SNF family complexes bind to a multitude of genomic loci, including distal enhancers, promoters and CCCTC-binding factor (CTCF)-binding sites (see Glossary), at which they facilitate and maintain DNA accessibility to regulate gene transcription. mSWI/SNF is often associated with promoting gene activation, but can also target to, and position, nucleosomes to enable the binding of repressive transcription factors (TFs) or to establish a repressive chromatin state [9.Rafati H. et al.Repressive LTR nucleosome positioning by the BAF complex is required for HIV latency.PLoS Biol. 2011; 9e1001206Crossref PubMed Scopus (97) Google Scholar].Table 1mSWI/SNF Complexes and FeaturesTable 1mSWI/SNF Complexes and FeaturesaSummary of genes encoding mSWI/SNF complex subunits, their aliases, and annotated domains from the InterPro database. The presence of each gene in specific mSWI/SNF complexes and modules is listed [24.Mashtalir N. et al.Modular organization and assembly of SWI/SNF family chromatin remodeling complexes.Cell. 2018; 175: 1272-1288Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar], along with associations with specific neurodevelopmental disorders and interacting TFs. Biogrid version 3.5.180 database [96.Shu X. et al.The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer: PBRM1 represses RLR signalling in CRC.J. Pathol. 2018; 244: 36-48Crossref PubMed Scopus (0) Google Scholar] was queried for literature-described interactions between components of the human mSWI/SNF complex and human TFs containing sequence-specific binding properties. Rows are shaded to group paralogs.bN.O.S., not otherwise specified.cPlease refer to the main text for additional details and references. aSummary of genes encoding mSWI/SNF complex subunits, their aliases, and annotated domains from the InterPro database. The presence of each gene in specific mSWI/SNF complexes and modules is listed [24.Mashtalir N. et al.Modular organization and assembly of SWI/SNF family chromatin remodeling complexes.Cell. 2018; 175: 1272-1288Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar], along with associations with specific neurodevelopmental disorders and interacting TFs. Biogrid version 3.5.180 database [96.Shu X. et al.The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer: PBRM1 represses RLR signalling in CRC.J. Pathol. 2018; 244: 36-48Crossref PubMed Scopus (0) Google Scholar] was queried for literature-described interactions between components of the human mSWI/SNF complex and human TFs containing sequence-specific binding properties. Rows are shaded to group paralogs. bN.O.S., not otherwise specified. cPlease refer to the main text for additional details and references. Multiple subunit positions within mSWI/SNF complexes are occupied by mutually exclusive paralogs. Lineage- or disease-specific gene expression programs can dictate which paralog is expressed or assembled into the specific complex. For example, PHF10 and DPF2 subunits are expressed and incorporated into embryonic stem cell- and neural progenitor-specific BAF complexes (esBAF or npBAF, respectively) as well as complexes found in most cell types, whereas DPF1 or DPF3 are exclusively incorporated into a postmitotic neuron-specific BAF complex (previously termed 'nBAF') [10.Son E.Y. Crabtree G.R. The role of BAF (mSWI/SNF) complexes in mammalian neural development.Am. J. Med. Genet. C: Semin. Med. Genet. 2014; 166C: 333-349Crossref PubMed Scopus (68) Google Scholar]. Additionally, a leukemia-specific BAF complex (leukBAF) was reported to preferentially contain ARID1A and SMARCA4 over their paralogs ARID1B and SMARCA2 [11.Buscarlet M. et al.Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance.Blood. 2014; 123: 1720-1728Crossref PubMed Scopus (59) Google Scholar]; however, these appear to be the dominant paralogs in most adult cell types. Advances in biochemical strategies as well as single-cell RNA-seq technologies will further increase our understanding of the cell-, tissue-, and disease-specific mSWI/SNF complexes, which could illuminate unique therapeutic opportunities (Box 1).Box 1Strategies for Discovering Novel Therapeutics Targeting mSWI/SNF ComplexesThe multimeric, combinatorically assembled mSWI/SNF complex can be targeted by multiple chemical approaches to achieve specific functional outcomes. First, use of mSWI/SNF complex-specific enzymatic inhibitors targeting the SMARCA2 and/or SMARCA4 ATPase/helicase subunits is implicated in multiple human cancers (see 'Targeting SMARCA4-mutant cancers' in the main text). SMARCA2 and SMARCA4 ATPase activators may also have clinical applications in diseases with partial loss of mSWI/SNF chromatin-remodeling functions. Second, multiple subunits of the mSWI/SNF complex contain highly conserved functional domains, particularly reader domains, that are involved in chromatin regulation. PBRM1, BRD7, BRD9, SMARCA2, and SMARCA4 are bromodomain-containing proteins; DPF1, DPF2, and DPF3, as well as PHF10, are PHD-finger containing proteins; SMARCC1 and SMARCC2 are chromodomain-containing proteins. These domains are ligandable and small-molecule binders to these domains can be explored for therapeutic use. Furthermore, small-molecule binders can be coupled, via a linker, to binding molecules of E3 ubiquitin ligases, such as Cereblon or VHL, to develop bifunctional degraders for targeted degradation of specific mSWI/SNF subunits for disease applications [8.Michel B.C. et al.A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation.Nat. Cell Biol. 2018; 20: 1410-1420Crossref PubMed Scopus (75) Google Scholar,45.Farnaby W. et al.BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.Nat. Chem. Biol. 2019; 15: 672-680Crossref PubMed Scopus (81) Google Scholar,64.Brien G.L. et al.Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma.Elife. 2018; 7e41305Crossref PubMed Scopus (35) Google Scholar]. Third, a multitude of disease-relevant transcription factors (TFs) recruit mSWI/SNF to drive disease-specific transcriptional programs through interactions with mSWI/SNF subunits (see 'Targeting oncogenic transcription factors' in the main text). Development of small-molecule inhibitors that selectively disrupt TF-mSWI/SNF binding is an attractive drug discovery approach to reverse or inhibit disease-driving transcriptional states. The multimeric, combinatorically assembled mSWI/SNF complex can be targeted by multiple chemical approaches to achieve specific functional outcomes. First, use of mSWI/SNF complex-specific enzymatic inhibitors targeting the SMARCA2 and/or SMARCA4 ATPase/helicase subunits is implicated in multiple human cancers (see 'Targeting SMARCA4-mutant cancers' in the main text). SMARCA2 and SMARCA4 ATPase activators may also have clinical applications in diseases with partial loss of mSWI/SNF chromatin-remodeling functions. Second, multiple subunits of the mSWI/SNF complex contain highly conserved functional domains, particularly reader domains, that are involved in chromatin regulation. PBRM1, BRD7, BRD9, SMARCA2, and SMARCA4 are bromodomain-containing proteins; DPF1, DPF2, and DPF3, as well as PHF10, are PHD-finger containing proteins; SMARCC1 and SMARCC2 are chromodomain-containing proteins. These domains are ligandable and small-molecule binders to these domains can be explored for therapeutic use. Furthermore, small-molecule binders can be coupled, via a linker, to binding molecules of E3 ubiquitin ligases, such as Cereblon or VHL, to develop bifunctional degraders for targeted degradation of specific mSWI/SNF subunits for disease applications [8.Michel B.C. et al.A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation.Nat. Cell Biol. 2018; 20: 1410-1420Crossref PubMed Scopus (75) Google Scholar,45.Farnaby W. et al.BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.Nat. Chem. Biol. 2019; 15: 672-680Crossref PubMed Scopus (81) Google Scholar,64.Brien G.L. et al.Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma.Elife. 2018; 7e41305Crossref PubMed Scopus (35) Google Scholar]. Third, a multitude of disease-relevant transcription factors (TFs) recruit mSWI/SNF to drive disease-specific transcriptional programs through interactions with mSWI/SNF subunits (see 'Targeting oncogenic transcription factors' in the main text). Development of small-molecule inhibitors that selectively disrupt TF-mSWI/SNF binding is an attractive drug discovery approach to reverse or inhibit disease-driving transcriptional states. Among the many chromatin modifiers and epigenetic regulators that have been identified as being mutated in cancer via large-scale cancer genome-sequencing studies [12.Bailey M.H. et al.Comprehensive characterization of cancer driver genes and mutations.Cell. 2018; 173: 371-385Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar] [The Cancer Genome Atlas (TCGA) Pan Cancer Atlas, MSK-IMPACT [13.Zehir A. et al.Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat. Med. 2017; 23: 703-713Crossref PubMed Scopus (1063) Google Scholar], Catalog of Somatic Mutations in Cancer (COSMIC) [14.Tate J.G. et al.COSMIC: the Catalogue Of Somatic Mutations In Cancer.Nucleic Acids Res. 2019; 47: D941-D947Crossref PubMed Scopus (607) Google Scholar]], the genes encoding members of mSWI/SNF complexes are mutated in >20% of human tumors collectively, making them the most frequently mutated chromatin-related cancer genes (Figure 1B) [15.Kadoch C. et al.Proteomic and bioinformatic analysis of mSWI/SNF (BAF) complexes reveals extensive roles in human malignancy.Nat. Genet. 2013; 45: 592-601Crossref PubMed Scopus (0) Google Scholar]. ARID1A, PBRM1, SMARCA4, and ARID2 are highly mutated in various common cancers and are currently included in cancer-sequencing panels for routine diagnostics. Interestingly, distinct mSWI/SNF complex members are mutated in different cancer subtypes (Figure 1C). For example, SMARCB1 loss is the genetic driver in malignant rhabdoid tumors (MRT), atypical teratoid/rhabdoid tumors, and >90% of epitheliod sarcomas [16.Biegel J.A. et al.Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors.Cancer Res. 1999; 59: 74-79PubMed Google Scholar, 17.Roberts C.W.M. et al.Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13796-13800Crossref PubMed Scopus (309) Google Scholar, 18.Sullivan L.M. et al.Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions.Mod. Pathol. 2013; 26: 385-392Crossref PubMed Scopus (81) Google Scholar], but its loss is rarely observed in other malignancies. Large-scale screening of human cancer cell lines for genetic dependencies has revealed SMARCB1 as an essential gene [19.Meyers R.M. et al.Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells.Nat. Genet. 2017; 49: 1779-1784Crossref PubMed Scopus (341) Google Scholar]. Likely, biallelic SMARCB1 loss is only tolerated in unique cell states or lineages to promote tumorigenesis, such as in the cell types leading to cancers driven by its loss. Mutation of PBRM1 is associated with >40% of clear cell renal cell carcinoma (ccRCC), but mutated in few other cancer types; and fusion of the SS18 subunit to SSX family members (SS18-SSX fusion oncoprotein) is the hallmark driver event only in synovial sarcoma [15.Kadoch C. et al.Proteomic and bioinformatic analysis of mSWI/SNF (BAF) complexes reveals extensive roles in human malignancy.Nat. Genet. 2013; 45: 592-601Crossref PubMed Scopus (0) Google Scholar]. ARID1A and SMARCA4 are frequently mutated in multiple cancer types, while their paralogs, ARID1B and SMARCA2, respectively, are mutated less frequently (Figure 1C). The mechanisms underlying the unexpected specificity of subunit mutations within defined cancer subtypes require further studies (see Outstanding Questions). Nevertheless, these observations have suggested unique therapeutic opportunities to target subunit dependencies in different human cancers. Given the large percentage of cancers that harbor loss-of-function mutations in genes encoding mSWI/SNF complex subunits that result in absent expression of the subunit at the protein level, there is significant interest in identifying vulnerabilities that are generated by these specific mutational contexts. Genome-scale cell line dependency screens using both clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 and short hairpin (sh)RNA, coupled with focused, hypothesis-directed experiments, and, in some cases, probe compound evaluation, have revealed several synthetic lethal relationships or context-specific subunit dependencies of interest in cancers with mSWI/SNF subunit mutations (Table 2).Table 2Cancer-Associated Mutant mSWI/SNF Complex Subunits and Targeted Therapeutic ModalitiesMutant complex memberAssociated cancersTherapeutic modalitiesARID1ABladder, stomach, endometrial, other solid tumorsbRefer to Figure 1C in the main text.ARID1B-selective degrader, EZH2 inhibitor, PI3K inhibitorSMARCA4Nonsmall cell lung carcinoma, and other solid tumorsbRefer to Figure 1C in the main text.SMARCA2-selective inhibitor or degrader, CDK4/6 inhibitorSMARCA2aSMARCA2 is frequently epigenetically silenced and low SMARCA2 expression confers a dependency on SMARCA4.EsophagealSMARCA4-selective inhibitor or degraderSS18-SSXSynovial sarcomaBRD9-selective degrader, SS18-SSX degraderSMARCB1Malignant rhabdoid tumor, epithelial sarcomaBRD9-selective degrader, EZH2 inhibitorPBRM1Kidney and other solid cancersbRefer to Figure 1C in the main text.Immune checkpoint agentsa SMARCA2 is frequently epigenetically silenced and low SMARCA2 expression confers a dependency on SMARCA4.b Refer to Figure 1C in the main text. Open table in a new tab ARID1A is the most frequently mutated mSWI/SNF gene across multiple cancer types. Large-scale shRNA and CRISPR screening efforts in human cancer cell lines [19.Meyers R.M. et al.Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells.Nat. Genet. 2017; 49: 1779-1784Crossref PubMed Scopus (341) Google Scholar, 20.Cheung H.W. et al.Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer.Proc. Natl. Acad. Sci. U. S. 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In the absence of ARID1A, ARID1B-containing mSWI/SNF complexes compensate to maintain genomic accessibility, particularly over the enhancers of genes important for cell proliferation and survival, such as MET and BCL2L1 [23.Kelso T.W.R. et al.Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers.eLife. 2017; 6e30506Crossref PubMed Google Scholar]. ARID1A and ARID1B share ~60% sequence identity and, in addition to the shared N-terminal DNA-binding ARID domain, both proteins contain a similar C-terminal domain, which was recently shown to make extensive contacts with other mSWI/SNF complex subunits, serving as a hub for complex assembly [24.Mashtalir N. et al.Modular organization and assembly of SWI/SNF family chromatin remodeling complexes.Cell. 2018; 175: 1272-1288Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. The lack of druggable domains on ARID1A and ARID1B has to date stifled efforts to develop a selective ARID1B inhibitor. However, if any small-molecule ligand were to demonstrate ARID1B binding, it could lead to the development of a selective ARID1B degrader as a novel therapy for ARID1A-mutant cancers. EZH2, encoding the catalytic component of Polycomb Repressive Complex 2 (PRC2), was reported to be synthetic lethal with ARID1A [25.Bitler B.G. et al.Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.Nat. Med. 2015; 21: 231-238Crossref PubMed Scopus (330) Google Scholar]. Pharmacological inhibition of EZH2 using GSK126, or EZH2 knockdown by shRNA, were shown to selectively inhibit the growth of ARID1A-mutant ovarian cancer cell lines [25.Bitler B.G. et al.Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.Nat. 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PRC2 and mSWI/SNF complexes have opposing effects on gene expression [26.Kennison J.A. Tamkun J.W. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila.Proc. Natl. Acad. Sci. 1988; 85: 8136-8140Crossref PubMed Google Scholar]. In the absence of ARID1A, EZH2 inhibition was suggested to result in tumor cell apoptosis through derepression of the tumor suppressor and inhibitor of PI3K/AKT signaling, PIK3IP1 [25.Bitler B.G. et al.Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.Nat. Med. 2015; 21: 231-238Crossref PubMed Scopus (330) Google Scholar]. Activating PI3KCA mutations commonly co-occur with ARID1A mutations in ovarian clear cell carcinoma [27.Chandler R.L. et al.Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signaling.Nat. 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This switch to SMARCA2 was associated with upregulation of the antiapoptotic gene, BCL2; and, subsequently, the acquired resistance could be overcome by treatment with ABT263, a small-molecule BCL2 antagonist [29.Wu S. et al.SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A -mutated cells.Nat. Commun. 2018; 94116Crossref PubMed Scopus (15) Google Scholar]. These results provide a rationale for combining an EZH2 inhibitor with a BCL2 antagonist for the treatment of ARID1A mutant cancers. In addition to transcriptional regulation, the mSWI/SNF complex has also been linked to DNA repair and maintenance of genomic integrity [30.Brownlee P.M. et al.The SWI/SNF chromatin remodelling complex: Its role in maintaining genome stability and preventing tumourigenesis.DNA Repair. 2015; 32: 127-133Crossref PubMed Scopus (50) Google Scholar]. mSWI/SNF promoted chromatin remodeling at sites of DNA double-strand breaks [31.Chai B. et al.Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA double-strand break repair.Genes Dev. 2005; 19: 1656-1661Crossref PubMed Scopus (233) Google Scholar,32.Park J.-H. et al.Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting γ-H2AX induction.EMBO J. 2006; 25: 3986-3997Crossref PubMed Scopus (0) Google Scholar] and several recent studies suggested that ARID1A loss renders cells more sensitive to DNA-damaging agents [33.Shen J. et al.ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors.Cancer Discov. 2015; 5: 752-767Crossref PubMed Scopus (177) Google Scholar, 34.Watanabe R. et al.SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability.Cancer Res. 2014; 74: 2465-2475Crossref PubMed Scopus (85) Google Scholar, 35.Park Y. et al.Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy.Clin. 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