Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press50710.17650/2313-805X-2023-10-1-8-17REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИTargeting of the SWI/SNF chromatin remodeling complex in cancer therapyТаргетирование комплекса ремоделирования хроматина SWI/SNF в терапии онкологических заболеванийhttps://orcid.org/0000-0002-2835-5992NemtsovaM. V.НемцоваМ. В.
Russian Federation

Marina Vyacheslavovna Nemtsova

Bld. 2, 8 Trubetskaya St., Moscow 119991

1 Moskvorechye St., Moscow 115478

Марина Вячеславовна Немцова

119991 Москва, ул. Трубецкая, 8, стр. 2

115478 Москва, ул. Москворечье, 1

nemtsova_m_v@mail.ruhttps://orcid.org/0000-0003-2043-5848BureI. V.БуреИ. В.
Russian Federation

Bld. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

I.M. Sechenov First Moscow State Medical University, Ministry of Health of RussiaФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова Минздрава РоссииResearch Centre for Medical GeneticsФГБНУ «Медико-генетический научный центр им. акад. Н.П. Бочкова»150120231018173003202330032023Copyright ©; 2023, Nemtsova M.V., Bure I.V.Copyright ©; 2023, Немцова М.В., Буре И.В.2023Nemtsova M.V., Bure I.V.Немцова М.В., Буре И.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/507

Chromatin remodeling is the one of the main epigenetic ways of gene expression regulation both in normal cells and in oncological diseases. Genes encoding protein subunits of SWI/ SNF remodeling complexes often mutate and/or change their expression in human tumors, affecting the expression programs of many genes during carcinogenesis, which is associated with the occurrence and progression of cancer. Today, there are no therapeutic drugs that could directly change the structure of chromatin because of complexity of this process with involvement of a large number of genes, proteins, non-coding transcripts and other intermediary molecules. However, the chromatin remodeling complexes can be affected by consistent influence on the subunits and the genes encoding them, as well as the non-coding RNAs that regulate the operation of these complexes and direct them to the target gene regions. Today, several successful strategies have been proposed to influence epigenetic regulators associated with chromatin in order to cause synthetic lethality of cancer cells and block tumor growth. To influence the processes of chromatin remodeling, various strategies and mechanisms are being investigated, from inhibitors of bromodomains of individual subunits to direct effects on the function of SWI/ SNF by destroying its main adenosine triphosphatase subunit. In our review, we analyze the ways and mechanisms of influencing the SWI/ SNF chromatin remodeling complex in order to obtain a stable antitumor effect, from experiments on tumor cells and animal models to the combined use of clinical drugs for the treatment of cancer patients.

Ремоделирование хроматина является одним из основных эпигенетических путей регуляции экспрессии генов как в норме, так и при онкологических заболеваниях. Гены, кодирующие белковые субъединицы комплексов ремоде­лирования sWI/sNF, часто мутируют и/или изменяют свою экспрессию в опухолях человека, влияя на программу экспрессии многих генов при канцерогенезе, что связано с возникновением и прогрессированием рака. Сегодня не существует терапевтических препаратов, которые бы непосредственно изменяли структуру хроматина, посколь­ку этот комплексный процесс требует привлечения большого количества генов, белков, некодирующих транскриптов и других молекул-посредников. Тем не менее воздействие на комплексы ремоделирования хроматина можно про­водить, последовательно влияя на субъединицы и кодирующие их гены, а также некодирующие РНк, которые регу­лируют работу данных комплексов и направляют их в районы генов-мишеней. предложены несколько успешных стратегий воздействия на эпигенетические регуляторы, связанные с хроматином, чтобы вызвать синтетическую летальность опухолевых клеток и блокировать опухолевый рост. для воздействия на процессы ремоделирования хроматина исследуют различные стратегии и механизмы: от ингибиторов бромодоменов отдельных субъединиц до прямого воздействия на функцию sWI/sNF посредством разрушения его основной субъединицы аденозинтри­фосфатазы.В обзоре подробно проанализированы пути и механизмы воздействия на комплекс ремоделирования хроматина sWI/sNF (от экспериментов на опухолевых клетках и модельных животных до сочетанного использования клини­ческих препаратов для лечения онкологических пациентов) с целью получения стойкого противоопухолевого эф­фекта.

chromatin remodelingSWI/ SNFsomatic mutationssynthetic lethality of cancer cellsbromodomain inhibitorsремоделирование хроматинаSWI/ SNFсоматические мутациисинтетическая летальность опухолевых клетокингибиторы бромодоменовThis work was supported by the Russian Science Foundation (project Ref. No. 20-75-10117).Работа выполнена при финансовой поддержке Российского научного фонда (грант № 20-75-10117).Kouzarides T. Chromatin modifications and their function. Cell 2007;128(4):693–705. DOI: 10.1016/j.cell.2007.02.005Patty B.J., Hainer S.J. Non-coding RNAs and nucleosome remodeling complexes: an intricate regulatory relationship. Biology 2020;9(8):213. DOI: 10.3390/biology9080213Sharma T. Cancer epigenetics: chromatin remodeling and other epigenetic mechanisms. In: Understanding cancer. Elsevier, 2022. Pp. 149–58.Clapier C.R., Iwasa J., Cairns B.R. et al. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol 2017;18(7):407–22. DOI: 10.1038/nrm. 2017.26Krishnamurthy N., Kato S., Lippman S. et al. Chromatin remodeling (SWI/SNF) complexes, cancer, and response to immunotherapy. J Immunother Cancer 2022;10:e004669. DOI:10.1136/jitc-2022-004669Mullen J., Kato S., Sicklick J.K. et al. Targeting ARID1A mutations in cancer. Cancer Treat Rev 2021;100:102287. DOI: 10.1016/ j.ctrv.2021.102287Wanior M., Krämer A., Knapp S. et al. Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy. Oncogene 2021;40(21):3637–54. DOI: 10.1038/s41388-021-01781-xMathur R. ARID1A loss in cancer: Towards a mechanistic understanding. Pharmacol Ther 2018;190:15–23. DOI: 10.1016/ j.pharmthera.2018.05.001Mashtalir N., Suzuki H., Farrell D.P. et al. A Structural model of the endogenous human BAF complex informs disease mechanisms. Cell 2020;183(3):802–17.e24. DOI: 10.1016/ j.cell.2020.09.051Sima X., He J., Peng J. et al. The genetic alteration spectrum of the SWI/SNF complex: the oncogenic roles of BRD9 and ACTL6A. PLoS One 2019;14(9):e0222305. DOI: 10.1371/journal. pone.0222305Torres-Martín M., Kusak M.E., Isla A. et al. Whole exome sequencing in a case of sporadic multiple meningioma reveals shared NF2, FAM109B, and TPRXL mutations, together with unique SMARCB1 alterations in a subset of tumor nodules. Cancer Genet 2015;208(6):327–32. DOI: 10.1016/j.cancergen.2015.03.012Tokunaga R., Xiu J., Goldberg R.M. et al. The impact of ARID1A mutation on molecular characteristics in colorectal cancer. Eur J Cancer 2020;140:119–29. DOI: 10.1016/j.ejca.2020.09.006Ahadi M.S., Fuchs T.L., Clarkson A. et al. Switch/sucrose-nonfermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)-deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas. Histopathology 2022;80(6):906–21. DOI: 10.1111/ his.14612Clarke B.A., Witkowski L., Ton Nu T.N. et al. Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics. Histopathology 2016;69(5):727–38. DOI: 10.1111/his.12988Wang J., Xi Z., Xi J. et al. Somatic mutations in renal cell carcinomas from Chinese patients revealed by whole exome sequencing. Cancer Cell Int 2018;18:159. DOI: 10.1186/s12935-018-0661-5Nargund A.M., Pham C.G., Dong Y. et al. The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep 2017;18(12):2893–906. DOI: 10.1016/j.celrep.2017.02.074Högner A., Krause H., Jandrig B. et al. PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient’s overall survival. Urol Oncol 2018;36(3):94.e1–14. DOI: 10.1016/j.urolonc.2017.10.027Braun D.A., Hou Y., Bakouny Z. et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med 2020;26(6):909–18. DOI: 10.1038/s41591-020-0839-yMiao D., Margolis C.A., Gao W. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 2018;359(6377):801–6. DOI: 10.1126/science. aan5951Liu X.-D., Kong W., Peterson C.B. et al. PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma. Nat Commun 2020;11(1):2135. DOI: 10.1038/s41467-020-15959-6Wu J.N., Roberts C.W.M. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov 2013;3(1):35–43. DOI: 10.1158/2159-8290.CD-12-0361Nemtsova M.V., Kalinkin A.I., Kuznetsova E.B. et al. Mutations in epigenetic regulation genes in gastric cancer. Cancers 2021;13(18):4586. DOI: 10.3390/cancers13184586Yamamoto H., Watanabe Y., Maehata T. et al. An updated review of gastric cancer in the next-generation sequencing era: insights from bench to bedside and vice versa. World J Gastroenterol 2014;20(14):3927–37. DOI: 10.3748/wjg.v20.i14.3927Li L., Li M., Jiang Z. et al. ARID1A Mutations are associated with increased immune activity in gastrointestinal cancer. Cells 2019;8(7):678. DOI: 10.3390/cells8070678Moe K.C., Maxwell J.N., Wang J. et al. The SWI/SNF ATPase BRG1 facilitates multiple pro-tumorigenic gene expression programs in SMARCB1-deficient cancer cells. Oncogenesis 2022;11(1):30. DOI: 10.1038/s41389-022-00406-6Oike T., Ogiwara H., Tominaga Y. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res 2013;73(17): 5508–18. DOI: 10.1158/0008-5472.CAN-12-4593Bitler B.G., Aird K.M., Zhang R. Epigenetic synthetic lethality in ovarian clear cell carcinoma: EZH2 and ARID1A mutations. Mol Cell Oncol 2016;3(1):e1032476. DOI: 10.1080/23723556.2015.1032476Huang K., Sun R., Chen J. et al. A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells. Cell Cycle 2020;19(7):758–71. DOI: 10.1080/15384101.2020.1729450Yamada L., Saito M., Thar Min A.K. et al. Selective sensitivity of EZH2 inhibitors based on synthetic lethality in ARID1Adeficient gastric cancer. Gastric Cancer 2021;24(1):60–71. DOI: 10.1007/s10120-020-01094-0Park Y., Chui M.H., Suryo Rahmanto Y. et al. Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy. Clin Cancer Res2019;25(18):5584–94. DOI: 10.1158/1078-0432.CCR-18-4222Park J.-H., Park E.-J., Lee H.-S. et al. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting γ-H2AX induction. EMBO J 2006;25(17):3986–97. DOI: 10.1038/sj.emboj.7601291Shen J., Peng Y., Wei L. et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov 2015;5(7):752–67. DOI: 10.1158/2159-8290.CD-14-0849Chabanon R.M., Morel D., Eychenne T. et al. PBRM1 deficiency confers synthetic lethality to DNA repair inhibitors in cancer. Cancer Res 2021;81(11):2888–902. DOI: 10.1158/0008-5472. CAN-21-0628Tsuda M., Fukuda A., Kawai M. et al. The role of the SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma. Cancer Sci 2021;112(2):490–7. DOI: 10.1111/cas.14768Zhou M., Yuan J., Deng Y. et al. Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers. Oncogenesis 2021;10(1):3. DOI: 10.1038/s41389-020-00296-6Pan D., Kobayashi A., Jiang P. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 2018;359(6377):770–5. DOI: 10.1126/science.aao1710Villarino A.V., Kanno Y., O’Shea J.J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 2017;18(4):374–84. DOI: 10.1038/ni.3691Leruste A., Tosello J., Ramos R.N. et al. Clonally expanded T cells reveal immunogenicity of rhabdoid tumors. Cancer Cell 2019;36(6):597–612.e8. DOI: 10.1016/j.ccell.2019.10.008Shen J., Ju Z., Zhao W. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 2018;24(5):556–62. DOI: 10.1038/s41591-018-0012-zJancewicz I., Szarkowska J., Konopinski R. et al. PD-L1 Overexpression, SWI/SNF Complex deregulation, and profound transcriptomic changes characterize cancer-dependent exhaustion of persistently activated CD4+ T Cells. Cancers 2021;13(16):4148. DOI: 10.3390/cancers13164148Carbognin L., Pilotto S., Milella M. et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One 2015;10(6):e0130142. DOI: 10.1371/journal.pone.0130142Cochran A.G., Conery A.R., Sims R.J. Bromodomains: a new target class for drug development. Nat Rev Drug Discov 2019;18(8):609–28. DOI: 10.1038/s41573-019-0030-7Vangamudi B., Paul T.A., Shah P.K. et al. The SMARCA2/4 ATPase domain surpasses the bromodomain as a drug target in SWI/SNFmutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res 2015;75(18):3865–78. DOI: 10.1158/0008- 5472.CAN-14-3798Papillon J.P.N., Nakajima K., Adair C.D. 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 2018;61(22):10155–72. DOI: 10.1021/acs.jmedchem.8b01318Rago F., Rodrigues L.U., Bonney M. et al. Exquisite sensitivity to dual BRG1/BRM ATPase inhibitors reveals broad SWI/SNF dependencies in acute myeloid leukemia. Mol Cancer Res 2022;20(3):361–72. DOI: 10.1158/1541-7786.MCR21-0390Xiao L., Parolia A., Qiao Y. et al. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. Nature 2022;601(7893): 434–9. DOI: 10.1038/s41586-021-04246-zSchick S., Grosche S., Kohl K.E. et al. Acute BAF perturbation causes immediate changes in chromatin accessibility. Nat Genet 2021;53(3):269–78. DOI: 10.1038/s41588-021-00777-3Iurlaro M., Stadler M.B., Masoni F. et al. Mammalian SWI/SNF continuously restores local accessibility to chromatin. Nat Genet 2021;53(3):279–87. DOI: 10.1038/s41588-020-00768-wSoldi R., Ghosh Halder T., Weston A. et al. The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/ Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer. PLoS One 2020;15(7):e0235705. DOI: 10.1371/journal. pone.0235705Patnaik S., Anupriya. Drugs targeting epigenetic modifications and plausible therapeutic strategies against colorectal cancer. Front Pharmacol 2019;10:588. DOI: 10.3389/fphar.2019.00588