RATIONAL COMBINATION OF ONCOLYTIC VIRUSES AND RAPAMYCIN ANALOGUES IN CANCER THERAPY (LITERATURE REVIEW)
Abstract
Malignant neoplasms are currently one of the main causes of death in most countries of the world, and therefore the issue of developing new drugs for the treatment of cancer is extremely acute. Among the possible promising ways to combat it, the use of drugs containing oncolytic viruses and drugs based on rapamycin attracts attention. Oncolytic viruses (viruses that mainly affect cancer cells) have a direct cytolytic effect, destroying a malignant tumor, and also stimulate the antitumor immunity of the body. Rapamycin is a potent inhibitor of the mTOR -mechanical (formerly mammalian) target of rapamycin signaling pathway. It has been proven that rapamycin and its analogues can be effectively used for the treatment and prevention of cancer, as well as affect the aging process. While each group of drugs individually has certain disadvantages, there is a possibility of leveling them when used together, which in a number of studies has shown a good therapeutic result. The synergistic effect of oncolytic viruses and rapamycin is primarily due to the ability of the latter to stimulate the replication of the virus in the affected cells, showing its own cytostatic effect in the unaffected ones. Replication stimulation can occur through Akt activation or through suppression of mTORC1-dependent interferon type I production. Also, the catalytic inhibitors mTORC1 and mTORC2 enhance the replication of the herpes simplex virus in cancer cells along the eIF4E/4EBP axis. The mechanisms of action of oncolytic viruses, rapamycin and their combinations on malignant cells are considered in this literature review.
References
Баранов И.А., Гладин Д.П., Козлова Н.С. Взаимосвязь гиперактивации сигнального пути mTOR, процессов старения и патогенеза COVID-19 (обзор литературы). Российские биомедицинские исследования. 2023; 8(2): 64–77.
Баранов И.А., Мелиева З.Ю., Мелиева Ф.Ю. Патологическая анатомия туберозного склероза. Интернаука. 2022; 38-1(261): 15–20.
Бородкина А.В., Дерябин П.И., Грюкова А.А., Никольский Н.Н. «Социальная жизнь» стареющих клеток: что такое SASP и зачем его изучать? Acta Naturae (русскоязычная версия). 2018; 1(36).
Давыдов М.И., Ганцев Ш.Х., Вельшер Л.З. и др. Онкология. М.: ГЭОТАР-Медиа; 2010.
Дементьева Е.А., Гурина О.П. Иммунологические изменения, сопровождающие развитие экспериментального неопластического процесса. Педиатр. 2015; 6(2): 96–108. DOI: 10.17816/PED6296-108.
Имянитов Е.Н., Хансон К.П. Молекулярная онкология: клинические аспекты. СПб.: Издательский дом СПбМАПО; 2007.
Москалев А.А. 120 лет жизни — только начало. Как победить старение? 2-е издание. М.: Эксмо; 2018.
Селезнева А.А., Козлова Н.С. Микробиота и рак: союзники или враги? Здоровье — основа человеческого потенциала: проблемы и пути их решения. 2022; 17(2): 774–81.
Alain T., Lun X., Martineau Y. et al. Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production. Proc Natl Acad Sci USA. 2010; 107(4): 1576–81. DOI: 10.1073/pnas.0912344107. Epub 2010 Jan 4.
Blagosklonny M.V. Cancer prevention with rapamycin. Oncotarget. 2023; 14: 342–50. DOI: 10.18632/oncotarget.28410.
Blagosklonny M.V. From causes of aging to death from COVID-19. Aging (Albany NY). 2020; 12(11): 10004–21. DOI: 10.18632/aging.103493. Epub 2020 Jun 12.
Chen X.G., Liu F., Song X.F. et al. Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways. Mol Carcinog. 2010; 49(6): 603–10. DOI: 10.1002/mc.20628.
Dominick G., Bowman J., Li X. et al. mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell. 2017; 16(1): 52–60. DOI: 10.1111/acel.12525. Epub 2016 Sep 13.
Dorrello N.V., Peschiaroli A., Guardavaccaro D. et al. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006; 314(5798): 467–71. DOI: 10.1126/science.1130276.
Fukuhara H., Ino Y., Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci. 2016; 107(10): 1373–9. DOI: 10.1111/cas.13027. Epub 2016 Sep 9.
García-Martínez J.M., Alessi D.R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008; 416(3): 375–85. DOI: 10.1042/BJ20081668.
Grabiner B.C., Nardi V., Birsoy K. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 2014; 4(5): 554–63. DOI: 10.1158/2159-8290.CD-13-0929. Epub 2014 Mar 14.
Granville C.A., Warfel N., Tsurutani J. et al. Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors. Clin Cancer Res. 2007; 13(7): 2281–9. DOI: 10.1158/1078-0432.CCR-06-2570.
Holz M.K., Ballif B.A., Gygi S.P., Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005; 123(4): 569–80. DOI: 10.1016/j.cell.2005.10.024.
Homicsko K., Lukashev A., Iggo R.D. RAD001 (everolimus) improves the efficacy of replicating adenoviruses that target colon cancer. Cancer Res. 2005; 65(15): 6882–90. DOI: 10.1158/0008-5472.CAN-05-0309.
Huang S. mTOR Signaling in Metabolism and Cancer. Cells. 2020; 9(10): 2278. DOI: 10.3390/cells9102278.
Javanbakht M., Tahmasebzadeh S., Cegolon L. et al. Oncolytic viruses: A novel treatment strategy for breast cancer. Genes Dis. 2021; 10(2): 430–46. DOI: 10.1016/j.gendis.2021.11.011.
Kaufman H.L., Kohlhapp F.J., Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015; 14(9): 642–62. DOI: 10.1038/nrd4663. Erratum in: Nat Rev Drug Discov. 2016; 15(9): 660.
Kim J., Kundu M., Viollet B., Guan K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011; 13(2): 132–41. DOI: 10.1038/ncb2152. Epub 2011 Jan 23.
Laberge R.M., Sun Y., Orjalo A.V. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015; 17(8): 1049–61. DOI: 10.1038/ncb3195. Epub 2015 Jul 6. Erratum in: Nat Cell Biol. 2021; 23(5): 564–5.
Lun X.Q., Zhou H., Alain T. et al. Targeting human medulloblastoma: oncolytic virotherapy with myxoma virus is enhanced by rapamycin. Cancer Res. 2007; 67(18): 8818–27. DOI: 10.1158/0008-5472.CAN-07-1214.
Ma X.M., Yoon S.O., Richardson C.J. et al. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell. 2008; 133(2): 303–13. DOI: 10.1016/j.cell.2008.02.031.
Mafi S., Mansoori B., Taeb S. et al. mTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment. Front Immunol. 2022; 12: 774103. DOI: 10.3389/fimmu.2021.774103.
Martina J.A., Chen Y., Gucek M., Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012; 8(6): 903–14. DOI: 10.4161/auto.19653. Epub 2012 May 11.
Melcher A., Parato K., Rooney C.M., Bell J.C. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011; 19(6): 1008–16. DOI: 10.1038/mt.2011.65. Epub 2011 Apr 19.
Mukhopadhyay S., Frias M.A., Chatterjee A. et al. The Enigma of Rapamycin Dosage. Mol Cancer Ther. 2016; 15(3): 347–53. DOI: 10.1158/1535-7163.MCT-15-0720. Epub 2016 Feb 25.
Popova N.V., Jücker M. The Role of mTOR Signaling as a Therapeutic Target in Cancer. Int J Mol Sci. 2021; 22(4): 1743. DOI: 10.3390/ijms22041743.
Powell J.D., Pollizzi K.N., Heikamp E.B., Horton M.R. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012; 30: 39–68. DOI: 10.1146/annurev-immunol-020711-075024. Epub 2011 Nov 29.
Powell J.D., Pollizzi K.N., Heikamp E.B., Horton M.R. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012; 30: 39–68. DOI: 10.1146/annurev-immunol-020711-075024. Epub 2011 Nov 29.
Rousseau A., Bertolotti A. An evolutionarily conserved pathway controls proteasome homeostasis. Nature. 2016; 536(7615): 184–9. DOI: 10.1038/nature18943. Epub 2016 Jul 27.
Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307(5712): 1098–101. DOI: 10.1126/science.1106148.
Saxton R.A., Sabatini D.M. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017; 168(6): 960–76. DOI: 10.1016/j.cell.2017.02.004. Erratum in: Cell. 2017; 169(2): 361–71.
Sokolenko A.P., Imyanitov E.N. Molecular diagnostics in clinical oncology. Frontiers in Molecular Biosciences. 2018; 5(AUG.): 76. DOI 10.3389/fmolb.2018.00076.
Stanford M.M., Barrett J.W., Nazarian S.H. et al. Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells. J Virol. 2007; 81(3): 1251–60. DOI: 10.1128/JVI.01408-06. Epub 2006 Nov 15.
Strong J.E., Coffey M.C., Tang D. et al. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 1998; 17(12): 3351–62. DOI: 10.1093/emboj/17.12.3351.
Thoreen C.C., Chantranupong L., Keys H.R. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012; 485(7396): 109–13. DOI: 10.1038/nature11083.
Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018; 64(2): 127–34. DOI: 10.1159/000484629. Epub 2017 Dec 1.
Werden S.J., Barrett J.W., Wang G. et al. M-T5, the ankyrin repeat, host range protein of myxoma virus, activates Akt and can be functionally replaced by cellular PIKE-A. J Virol. 2007; 81(5): 2340–8. DOI: 10.1128/JVI.01310-06. Epub 2006 Dec 6.
Yu Z., Chan M.K., O-charoenrat P. et al. Enhanced nectin-1 expression and herpes oncolytic sensitivity in highly migratory and invasive carcinoma. Clin Cancer Res. 2005; 11(13): 4889–97. DOI: 10.1158/1078-0432.CCR-05-0309.
Zakaria C., Sean P., Hoang H.D. et al. Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis. PLoS Pathog. 2018; 14(8): e1007264. DOI: 10.1371/journal.ppat.1007264.
Zhu Z., McGray A.J.R., Jiang W. et al. Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer. 2022; 21(1): 196. DOI: 10.1186/s12943-022-01664-z.
Copyright (c) 2024 Russian Biomedical Research

This work is licensed under a Creative Commons Attribution 4.0 International License.