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U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>Activation of endogenous retrotransposons frequently occurs in cancer cells and contributes to tumor genomic instability. To test whether inhibition of retrotranspositions has an anticancer effect, we used treatment with the nucleoside reverse transcriptase inhibitor (NRTI) stavudine (STV) in mouse cancer models, MMTV-HER2\/Neu and Th-MYCN, that spontaneously develop breast cancer and neuroblastoma, respectively. In both cases, STV in drinking water did not affect tumor incidence nor demonstrate direct antitumor effects. However, STV dramatically extended progression-free survival in both models following an initial complete response to chemotherapy. To approach the mechanism underlying this phenomenon, we analyzed the effect of NRTI on the selection of treatment-resistant variants in tumor cells in culture. Cultivation of mouse breast carcinoma 4T1 in the presence of STV dramatically reduced the frequency of cells capable of surviving treatment with anticancer drugs. Global transcriptome analysis demonstrated that the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-\u03baB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-\u03baB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population. These results indicate a mechanism by which retrotransposon desilencing can stimulate tumor cell survival during treatment and suggest reverse transcriptase inhibition as a potential therapeutic approach for targeting the development of drug-resistant cancers.<\/jats:p>","DOI":"10.1073\/pnas.2213146119","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T13:37:53Z","timestamp":1669815473000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":21,"title":["Inflammatory response to retrotransposons drives tumor drug resistance that can be prevented by reverse transcriptase inhibitors"],"prefix":"10.1073","volume":"119","author":[{"given":"Ksenia A.","family":"Novototskaya-Vlasova","sequence":"first","affiliation":[{"name":"Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolay S.","family":"Neznanov","sequence":"additional","affiliation":[{"name":"Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Molodtsov","sequence":"additional","affiliation":[{"name":"Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1650-7191","authenticated-orcid":false,"given":"Brandon M.","family":"Hall","sequence":"additional","affiliation":[{"name":"Genome Protection, Inc., Buffalo, NY 14263"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mairead","family":"Commane","sequence":"additional","affiliation":[{"name":"Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-0826","authenticated-orcid":false,"given":"Anatoli S.","family":"Gleiberman","sequence":"additional","affiliation":[{"name":"Genome Protection, Inc., Buffalo, NY 14263"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayne","family":"Murray","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Research Centre, Sydney, NSW  2052, Australia"},{"name":"School of Clinical Medicine, UNSW Medicine &amp; Health, University of New South Wales, Sydney 2052, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2036-8817","authenticated-orcid":false,"given":"Michelle","family":"Haber","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Research Centre, Sydney, NSW  2052, Australia"},{"name":"School of Clinical Medicine, UNSW Medicine &amp; Health, University of New South Wales, Sydney 2052, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0632-4589","authenticated-orcid":false,"given":"Murray D.","family":"Norris","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Research Centre, Sydney, NSW  2052, Australia"},{"name":"University of New South Wales Centre for Childhood Cancer Research, Sydney 2052, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina I.","family":"Leonova","sequence":"additional","affiliation":[{"name":"Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei V.","family":"Gudkov","sequence":"additional","affiliation":[{"name":"Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203"},{"name":"Genome Protection, Inc., Buffalo, NY 14263"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17111942"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.15171\/apb.2017.041"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10762"},{"key":"e_1_3_4_4_2","first-page":"140","article-title":"Molecular mechanism of multidrug resistance in tumor cells","volume":"5","author":"Roninson I.","year":"1987","unstructured":"I. 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