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Parallel studies examined induction of cell death, STAT3 DNA binding activity, and expression of STAT3 downstream targets (BCL-X\n                      <jats:sub>L<\/jats:sub>\n                      , MCL-1, c-MYC). Validation was obtained in ATR shRNA knock-down cells, and in cells ectopically expressing BCL-X\n                      <jats:sub>L<\/jats:sub>\n                      , MCL-1, or c-MYC. Analogous studies were performed in primary MM cells and in a MM xenograft model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multiple pharmacologic ATR inhibitors inhibited STAT3 Tyr705 (but not Ser727) phosphorylation at low uM concentrations and down-regulated BCL-X\n                      <jats:sub>L<\/jats:sub>\n                      , MCL-1, c-MYC in association with cell death induction. Compatible results were observed in ATR shRNA knock-down cells. Cell death induced by ATR inhibitors was significantly attenuated in cells ectopically expressing constitutively active STAT3, BCL-X\n                      <jats:sub>L<\/jats:sub>\n                      , MCL-1, or c-MYC. Concordant results were observed in primary human MM cells and in an in vivo MM xenograft model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, these findings argue for a non-canonical role for the ATR kinase in STAT3 activation in MM cells, and suggest that STAT3 inactivation contributes to the lethal actions of ATR inhibitors in MM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s13402-023-00817-6","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:01:32Z","timestamp":1682899292000},"page":"1369-1380","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells"],"prefix":"10.1007","volume":"46","author":[{"given":"Lin","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jewel","family":"Nkwocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanika","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Kmieciak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hashim","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5457-7532","authenticated-orcid":false,"given":"Liang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4452-9320","authenticated-orcid":false,"given":"Steven","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,1]]},"reference":[{"key":"817_CR1","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1038\/s41568-018-0034-3","volume":"18","author":"E Lecona","year":"2018","unstructured":"E. 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These studies were conducted in accordance with recognized ethical guidelines (e.g., the Declaration of Helsinki).All animal studies were performed under protocol AD10000035, approved by our local IACUC, and regulated by VCU\u2019s Animal Care and Use Program, in accordance with AAALAC, USDA, and PHS guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict interests"}}]}}