Cancer genome-sequencing studies have revealed a remarkably high prevalence of mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes, with nearly 25% of all cancers harbouring aberrations in one or more of these genes. A role for such aberrations in tumorigenesis is evidenced by cancer predisposition in both carriers of germline loss-of-function mutations and genetically engineered mouse models with inactivation of any of several SWI/SNF subunits. Whereas many of the most frequently mutated oncogenes and tumour-suppressor genes have been studied for several decades, the cancer-promoting role of mutations in SWI/SNF genes has been recognized only more recently, and thus comparatively less is known about these alterations. Consequently, increasing research interest is being focused on understanding the prognostic and, in particular, the potential therapeutic implications of mutations in genes encoding SWI/SNF subunits. Herein, we review the burgeoning data on the mechanisms by which mutations affecting SWI/SNF complexes promote cancer and describe promising emerging opportunities for targeted therapy, including immunotherapy with immune-checkpoint inhibitors, presented by these mutations. We also highlight ongoing clinical trials open specifically to patients with cancers harbouring mutations in certain SWI/SNF genes.
At least nine different genes encoding subunits of the SWI/SNF family of chromatin-remodelling complexes are recurrently mutated in cancer, and these mutations are collectively present in nearly 25% of cancers.
Mutations in specific SWI/SNF genes are enriched in particular cancer types, suggesting differential roles for individual SWI/SNF components; consistent with this hypothesis, different SWI/SNF gene mutations confer distinct cancer vulnerabilities in mouse models.
The tumour-suppressor activity of the SWI/SNF chromatin-regulatory complexes is most likely attributable to their roles in facilitating transcription factor function, which is central to cell-fate specification; however, roles of the complexes in facilitating DNA repair might also contribute.
The identification of potential therapeutic vulnerabilities that arise from SWI/SNF gene mutations is leading to new areas of clinical investigation, including studies of immunotherapy in addition to kinase inhibitors and agents targeting mediators of DNA damage repair.
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Shain, A. H. & Pollack, J. R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One 8, e55119 (2013).
Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).
Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).
Roberts, C. W., Leroux, M. M., Fleming, M. D. & Orkin, S. H. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2, 415–425 (2002).
Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).
Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).
Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).
Euskirchen, G., Auerbach, R. K. & Snyder, M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J. Biol. Chem. 287, 30897–30905 (2012).
Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E. & Green, M. R. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370, 477–481 (1994).
Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15, 5370–5382 (1996).
Lemon, B., Inouye, C., King, D. S. & Tjian, R. Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 414, 924–928 (2001).
Raab, J. R., Resnick, S. & Magnuson, T. Genome-wide transcriptional regulation mediated by biochemically distinct SWI/SNF complexes. PLoS Genet. 11, e1005748 (2015).
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. 293, 3892–3903 (2018).
Brien, G. L. et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. eLife 7, e41305 (2018).
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. 20, 1410–1420 (2018).
Wang, X. et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nat. Commun. 10, 1881 (2019).
Mashtalir, N. et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175, 1272–1288.e20 (2018).
Cairns, B. R., Kim, Y. J., Sayre, M. H., Laurent, B. C. & Kornberg, R. D. A multisubunit complex containing the SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 gene products isolated from yeast. Proc. Natl Acad. Sci. USA 91, 1950–1954 (1994).
Neigeborn, L. & Carlson, M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics 108, 845–858 (1984).
Stern, M., Jensen, R. & Herskowitz, I. Five SWI genes are required for expression of the HO gene in yeast. J. Mol. Biol. 178, 853–868 (1984).
Martens, J. A., Wu, P. Y. & Winston, F. Regulation of an intergenic transcript controls adjacent gene transcription in Saccharomyces cerevisiae. Genes Dev. 19, 2695–2704 (2005).
Mathur, R. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat. Genet. 49, 296–302 (2017).
Wang, X. et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat. Genet. 49, 289–295 (2017).
Nakayama, R. T. et al. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat. Genet. 49, 1613–1623 (2017).
Alver, B. H. et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat. Commun. 8, 14648 (2017).
Lu, C. & Allis, C. D. SWI/SNF complex in cancer. Nat. Genet. 49, 178–179 (2017).
Gatchalian, J. et al. A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells. Nat. Commun. 9, 5139 (2018).
Hodges, C., Kirkland, J. G. & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, a026930 (2016).
Ogiwara, H. et al. Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. Oncogene 30, 2135–2146 (2011).
Qi, W. et al. BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51. J. Cell Sci. 128, 317–330 (2015).
Chen, Y. et al. A PARP1–BRG1–SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites. Nucleic Acids Res. 47, 8563–8580 (2019).
Brownlee, P. M., Meisenberg, C. & Downs, J. A. The SWI/SNF chromatin remodelling complex: its role in maintaining genome stability and preventing tumourigenesis. DNA Repair 32, 127–133 (2015).
Chabanon, R. M., Morel, D. & Postel-Vinay, S. Exploiting epigenetic vulnerabilities in solid tumors: novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin. Cancer Biol. 61,180–198 (2019).
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. 74, 2465–2475 (2014).
Park, J. H. et al. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO J. 25, 3986–3997 (2006).
Shen, J. et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 5, 752–767 (2015).
Dykhuizen, E. C. et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature 497, 624–627 (2013).
Zhao, B. et al. ARID1A promotes genomic stability through protecting telomere cohesion. Nat. Commun. 10, 4067 (2019).
Kakarougkas, A. et al. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol. Cell 55, 723–732 (2014).
Brownlee, P. M., Chambers, A. L., Cloney, R., Bianchi, A. & Downs, J. A. BAF180 promotes cohesion and prevents genome instability and aneuploidy. Cell Rep. 6, 973–981 (2014).
Biegel, J. A. et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).
Sevenet, N. et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65, 1342–1348 (1999).
Finetti, M. A., Grabovska, Y., Bailey, S. & Williamson, D. Translational genomics of malignant rhabdoid tumours: current impact and future possibilities. Semin. Cancer Biol.61, 20–41 (2020).
Roberts, C. W., Galusha, S. A., McMenamin, M. E., Fletcher, C. D. & Orkin, S. H. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc. Natl Acad. Sci. USA 97, 13796–13800 (2000).
Guidi, C. J. et al. Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol. Cell Biol. 21, 3598–3603 (2001).
Klochendler-Yeivin, A. et al. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500–506 (2000).
Han, Z. Y. et al. The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation. Nat. Commun. 7, 10421 (2016).
Brennan, B., Stiller, C. & Bourdeaut, F. Extracranial rhabdoid tumours: what we have learned so far and future directions. Lancet Oncol. 14, e329–e336 (2013).
Hasselblatt, M. et al. SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol. 128, 453–456 (2014).
Lu, B. & Shi, H. An in-depth look at small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): clinical implications from recent molecular findings. J. Cancer 10, 223–237 (2019).
Karnezis, A. N. et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 238, 389–400 (2016).
Kahali, B. et al. The silencing of the SWI/SNF subunit and anticancer gene BRM in rhabdoid tumors. Oncotarget 5, 3316–3332 (2014).
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
Sima, X. et al. The genetic alteration spectrum of the SWI/SNF complex: the oncogenic roles of BRD9 and ACTL6A. PLoS One 14, e0222305 (2019).
Hu, Z. et al. Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. Nat. Commun. 10, 733 (2019).
Hodges, H. C. et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat. Struct. Mol. Biol. 25, 61–72 (2018).
Gu, Y. F. et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov. 7, 900–917 (2017).
Bultman, S. J. et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 27, 460–468 (2008).
Kadoch, C. & Crabtree, G. R. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 153, 71–85 (2013).
McBride, M. J. et al. The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell 33, 1128–1141.e7 (2018).
Tsurusaki, Y. et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat. Genet. 44, 376–378 (2012).
Van Houdt, J. K. et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat. Genet. 44, 445–449, S1 (2012).
Orlando, K. A., Nguyen, V., Raab, J. R., Walhart, T. & Weissman, B. E. Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities. Expert Rev. Anticancer Ther. 19, 375–391 (2019).
Stern, C. Boveri and the early days of genetics. Nature 166, 446 (1950).
Lazzerini-Denchi, E. & Sfeir, A. Stop pulling my strings — what telomeres taught us about the DNA damage response. Nat. Rev. Mol. Cell Biol. 17, 364–378 (2016).
Li, S. K. H. & Martin, A. Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol. Med. 22, 274–289 (2016).
Lee, R. S. et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J. Clin. Invest. 122, 2983–2988 (2012).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Creighton, C. J. et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).
Ramos, P. et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 46, 427–429 (2014).
Yates, L. R. et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32, 169–184.e7 (2017).
Gibson, W. J. et al. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat. Genet. 48, 848–855 (2016).
Betz, B. L., Strobeck, M. W., Reisman, D. N., Knudsen, E. S. & Weissman, B. E. Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB. Oncogene 21, 5193–5203 (2002).
Wang, X. et al. TCR-dependent transformation of mature memory phenotype T cells in mice. J. Clin. Invest. 121, 3834–3845 (2011).
Look, A. T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059–1064 (1997).
Andersson, A. K. et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat. Genet. 47, 330–337 (2015).
Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).
van der Weyden, L. et al. Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5+/– leukemia. BMC Cancer 15, 585 (2015).
Aster, J. C. et al. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol. Cell Biol. 20, 7505–7515 (2000).
Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).
Condorelli, G. L. et al. T-cell-directed TAL-1 expression induces T-cell malignancies in transgenic mice. Cancer Res. 56, 5113–5119 (1996).
Peterson, C. L. & Herskowitz, I. Characterization of the yeast SWI1, SWI2, and SWI3 genes, which encode a global activator of transcription. Cell 68, 573–583 (1992).
Savas, S. & Skardasi, G. The SWI/SNF complex subunit genes: their functions, variations, and links to risk and survival outcomes in human cancers. Crit. Rev. Oncol. Hematol. 123, 114–131 (2018).
Endo, M. et al. Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma. Liver Int. 33, 105–117 (2013).
Cho, H. et al. Loss of ARID1A/BAF250a expression is linked to tumor progression and adverse prognosis in cervical cancer. Hum. Pathol. 44, 1365–1374 (2013).
Faraj, S. F. et al. ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder. Hum. Pathol. 45, 2233–2239 (2014).
Bai, J. et al. BRG1 is a prognostic marker and potential therapeutic target in human breast cancer. PLoS One 8, e59772 (2013).
Kaufmann, B. et al. BRG1 promotes hepatocarcinogenesis by regulating proliferation and invasiveness. PLoS One 12, e0180225 (2017).
Zhu, P. et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat. Commun. 7, 13608 (2016).
Agaimy, A. SWI/SNF complex-deficient soft tissue neoplasms: a pattern-based approach to diagnosis and differential diagnosis. Surg. Pathol. Clin. 12, 149–163 (2019).
Hadfield, K. D. et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J. Med. Genet. 45, 332–339 (2008).
Smith, M. J. et al. Expression of SMARCB1 (INI1) mutations in familial schwannomatosis. Hum. Mol. Genet. 21, 5239–5245 (2012).
Smith, M. J., Wallace, A. J., Bowers, N. L., Eaton, H. & Evans, D. G. SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genet. 207, 373–378 (2014).
Bourdeaut, F. et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin. Cancer Res. 17, 31–38 (2011).
Anaya, J., Reon, B., Chen, W. M., Bekiranov, S. & Dutta, A. A pan-cancer analysis of prognostic genes. PeerJ 3, e1499 (2015).
Agaimy, A. & Foulkes, W. D. Hereditary SWI/SNF complex deficiency syndromes. Semin. Diagn. Pathol. 35, 193–198 (2018).
Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).
Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301 (2012).
Gibson, W. T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2012).
Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).
Wang, X. et al. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res. 69, 8094–8101 (2009).
Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).
Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73, 5508–5518 (2013).
Papillon, J. P. N. et al. Discovery of orally active inhibitors of brahma homolog (BRM)/SMARCA2 ATPase activity for the treatment of brahma related gene 1 (BRG1)/SMARCA4-mutant cancers. J. Med. Chem. 61, 10155–10172 (2018).
Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 15, 672–680 (2019).
Winter, G. E. et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).
Zengerle, M., Chan, K. H. & Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10, 1770–1777 (2015).
Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755–763 (2015).
Reisman, D. N., Sciarrotta, J., Wang, W., Funkhouser, W. K. & Weissman, B. E. Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res. 63, 560–566 (2003).
Shorstova, T. et al. SWI/SNF-compromised cancers are susceptible to bromodomain inhibitors. Cancer Res. 79, 2761–2774 (2019).
Hohmann, A. F. et al. Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition. Nat. Chem. Biol. 12, 672–679 (2016).
Theodoulou, N. H. et al. Discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition. J. Med. Chem. 59, 1425–1439 (2016).
Kennison, J. A. & Tamkun, J. W. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proc. Natl Acad. Sci. USA 85, 8136–8140 (1988).
Tamkun, J. W. et al. Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561–572 (1992).
Wilson, B. G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010).
Erkek, S. et al. Comprehensive analysis of chromatin states in atypical teratoid/rhabdoid tumor identifies diverging roles for SWI/SNF and polycomb in gene regulation. Cancer Cell 35, 95–110.e8 (2019).
Kadoch, C. et al. Dynamics of BAF-polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat. Genet. 49, 213–222 (2017).
Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).
Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).
Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).
Italiano, A. et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 19, 649–659 (2018).
Kawano, S. et al. Preclinical evidence of anti-tumor activity induced by EZH2 inhibition in human models of synovial sarcoma. PLoS One 11, e0158888 (2016).
Kurmasheva, R. T. et al. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the pediatric preclinical testing program. Pediatr. Blood Cancer 64, 26218 (2017).
Knutson, S. K. et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA 110, 7922–7927 (2013).
Le Loarer, F. et al. Consistent SMARCB1 homozygous deletions in epithelioid sarcoma and in a subset of myoepithelial carcinomas can be reliably detected by FISH in archival material. Genes Chromosomes Cancer 53, 475–486 (2014).
Maruyama, D. et al. First-in-human study of the EZH1/2 dual inhibitor DS-3201b in patients with relapsed or refractory non-Hodgkin lymphomas — preliminary results. Blood 130, 4070–4070 (2017).
Mohammad, H. P., Barbash, O. & Creasy, C. L. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nat. Med. 25, 403–418 (2019).
Torchia, J. et al. Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell 30, 891–908 (2016).
Knipstein, J. A. et al. Histone deacetylase inhibition decreases proliferation and potentiates the effect of ionizing radiation in atypical teratoid/rhabdoid tumor cells. Neuro Oncol. 14, 175–183 (2012).
Fukumoto, T. et al. Repurposing pan-HDAC inhibitors for ARID1A-mutated ovarian cancer. Cell Rep. 22, 3393–3400 (2018).
Johann, P. D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016).
Ho, B. et al. Molecular subgrouping of atypical teratoid/rhabdoid tumors (ATRT) — a reinvestigation and current consensus. Neuro Oncol. https://doi.org/10.1093/neuonc/noz235 (2019).
Chun, H. E. et al. Genome-wide profiles of extra-cranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways. Cancer Cell 29, 394–406 (2016).
Weissmiller, A. M. et al. Inhibition of MYC by the SMARCB1 tumor suppressor. Nat. Commun. 10, 2014 (2019).
Jagani, Z. et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat. Med. 16, 1429–1433 (2010).
Alimova, I. et al. Inhibition of MYC attenuates tumor cell self-renewal and promotes senescence in SMARCB1-deficient group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo. Int. J. Cancer 144, 1983–1995 (2019).
Venkataraman, S. et al. Targeting aurora kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells. J. Neurooncol 107, 517–526 (2012).
Xue, Y. et al. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat. Commun. 10, 557 (2019).
Xue, Y. et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat. Commun. 10, 558 (2019).
Tagal, V. et al. SMARCA4-inactivating mutations increase sensitivity to aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nat. Commun. 8, 14098 (2017).
Geoerger, B. et al. A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors. Clin. Cancer Res. 23, 2433–2441 (2017).
Mosse, Y. P. et al. A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children’s Oncology Group Phase I and pilot consortium (ADVL0921). Clin. Cancer Res. 25, 3229–3238 (2019).
Oberlick, E. M. et al. Small-molecule and CRISPR screening converge to reveal receptor tyrosine kinase dependencies in pediatric rhabdoid tumors. Cell Rep. 28, 2331–2344.e8 (2019).
Chauvin, C. et al. High-throughput drug screening identifies pazopanib and clofilium tosylate as promising treatments for malignant rhabdoid tumors. Cell Rep. 21, 1737–1745 (2017).
Wong, J. P. et al. Dual targeting of PDGFRalpha and FGFR1 displays synergistic efficacy in malignant rhabdoid tumors. Cell Rep. 17, 1265–1275 (2016).
Miller, R. E. et al. Synthetic lethal targeting of ARID1A-mutant ovarian clear cell tumors with dasatinib. Mol. Cancer Ther. 15, 1472–1484 (2016).
Lang, J. D. et al. Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition. Clin. Cancer Res. 24, 1932–1943 (2018).
Yamamoto, S., Tsuda, H., Takano, M., Tamai, S. & Matsubara, O. PIK3CA mutations and loss of ARID1A protein expression are early events in the development of cystic ovarian clear cell adenocarcinoma. Virchows Arch. 460, 77–87 (2012).
Bosse, T. et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer. Mod. Pathol. 26, 1525–1535 (2013).
St Pierre, R. & Kadoch, C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr. Opin. Genet. Dev. 42, 56–67 (2017).
Samartzis, E. P. et al. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget 5, 5295–5303 (2014).
Dal Molin, M. et al. Loss of expression of the SWI/SNF chromatin remodeling subunit BRG1/SMARCA4 is frequently observed in intraductal papillary mucinous neoplasms of the pancreas. Hum. Pathol. 43, 585–591 (2012).
Zhang, Q. et al. Chromatin remodeling gene AT-rich interactive domain-containing protein 1A suppresses gastric cancer cell proliferation by targeting PIK3CA and PDK1. Oncotarget 7, 46127–46141 (2016).
Yap, T. A., Bjerke, L., Clarke, P. A. & Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharmacol. 23, 98–107 (2015).
Ding, Y. et al. Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer. J. Clin. Invest. 129, 759–773 (2019).
Howard, T. P. et al. MDM2 and MDM4 are therapeutic vulnerabilities in malignant rhabdoid tumors. Cancer Res. 79, 2404–2414 (2019).
Carugo, A. et al. p53 is a master regulator of proteostasis in SMARCB1-deficient malignant rhabdoid tumors. Cancer Cell 35, 204–220.e9 (2019).
Williamson, C. T. et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat. Commun. 7, 13837 (2016).
Park, Y. et al. Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy. Clin. Cancer Res. 25, 5584–5594 (2019).
Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).
Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).
Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).
Ashizawa, M. et al. Prognostic role of ARID1A negative expression in gastric cancer. Sci. Rep. 9, 6769 (2019).
Buglioni, S. et al. The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression. Oncoimmunology 7, e1457602 (2018).
Kim, Y. B., Ahn, J. M., Bae, W. J., Sung, C. O. & Lee, D. Functional loss of ARID1A is tightly associated with high PD-L1 expression in gastric cancer. Int. J. Cancer 145, 916–926 (2019).
Jiang, T., Chen, X., Su, C., Ren, S. & Zhou, C. Pan-cancer analysis of ARID1A alterations as biomarkers for immunotherapy outcomes. J. Cancer 11, 776–780 (2020).
Leruste, A. et al. Clonally expanded t cells reveal immunogenicity of rhabdoid tumors. Cancer Cell36, 597–612 (2019).
Chun, H. E. et al. Identification and analyses of extra-cranial and cranial rhabdoid tumor molecular subgroups reveal tumors with cytotoxic T cell infiltration. Cell Rep. 29, 2338–2354.e7 (2019).
Forrest, S. J. et al. Genomic and immunologic characterization of INI1-deficient pediatric cancers. Clin. Cancer Res. 26, CCR-19-3089 (2020).
Jelinic, P. et al. Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade. J. Natl Cancer Inst. 110, 787–790 (2018).
McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).
Keenan, T. E., Burke, K. P. & Van Allen, E. M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25, 389–402 (2019).
Schick, S. et al. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat. Genet. 51, 1399–1410 (2019).
The work of C.W.M.R. is supported by grants from the US National Institutes of Health (R01CA172152 and R01CA113794), Cure AT/RT Now, the Avalanna Fund, the Garrett B. Smith Foundation and American Lebanese Syrian Associated Charities (ALSAC) of the St. Jude Children’s Research Hospital. The authors thank S. Throm of the St. Jude Children’s Research Hospital for her insights and K. A. Laycock, also of the St. Jude Children’s Research Hospital, for scientific editing of the manuscript.
Nature Reviews Clinical Oncology thanks Michael C. Frühwald and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
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Mittal, P., Roberts, C.W.M. The SWI/SNF complex in cancer — biology, biomarkers and therapy. Nat Rev Clin Oncol 17, 435–448 (2020). https://doi.org/10.1038/s41571-020-0357-3
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