{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T23:02:51Z","timestamp":1771110171870,"version":"3.50.1"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    Mechanisms underlying potentiation of the anti\u2010myeloma (MM) activity of ataxia telangiectasia Rad3 (ATR) antagonists by MAPK (Mitogen\u2010activated protein kinases)\u2010related extracellular kinase 1\/2 (MEK1\/2) inhibitors were investigated. Co\u2010administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1\/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines. Mechanistically, BAY and cobimetinib blocked STAT3 Tyr705 and Ser727 phosphorylation, respectively, and dual dephosphorylation triggered marked STAT3 inactivation and downregulation of STAT3 (Signal transducer and activator of transcription 3) downstream targets (c\u2010Myc and BCL\u2010X\n                    <jats:sub>L<\/jats:sub>\n                    ). Similar events occurred in highly bortezomib\u2010resistant (PS\u2010R) cells, in the presence of patient\u2010derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1\/2 (trametinib) inhibitors. Notably, constitutively active STAT3 c\u2010MYC or BCL\u2010X\n                    <jats:sub>L<\/jats:sub>\n                    ectopic expression significantly protected cells from BAY\/cobimetinib. In contrast, transfection of cells with a dominant\u2010negative form of STAT3 (Y705F) sensitized cells to cobimetinib, as did ATR shRNA knockdown. Conversely, MEK1\/2 knockdown markedly increased ATRi sensitivity. The BAY\/cobimetinib regimen was also active against primary CD138\n                    <jats:sup>+<\/jats:sup>\n                    MM cells, but not normal CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells. Finally, the ATR inhibitor\/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib\u2010resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR\/MEK1\/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.\n                  <\/jats:p>","DOI":"10.1111\/bjh.19796","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T20:38:57Z","timestamp":1728419937000},"page":"2338-2348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined MEK1\/2 and ATR inhibition promotes myeloma cell death through a STAT3\u2010dependent mechanism in\u00a0vitro and in\u00a0vivo"],"prefix":"10.1111","volume":"205","author":[{"given":"Lin","family":"Li","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jewel","family":"Nkwocha","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Kmieciak","sequence":"additional","affiliation":[{"name":"Massey Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark B.","family":"Meads","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology H. Lee Moffitt Cancer Center  Tampa Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth H.","family":"Shain","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology H. Lee Moffitt Cancer Center  Tampa Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghunandan R.","family":"Alugubelli","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology H. Lee Moffitt Cancer Center  Tampa Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariosto S.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Physiology H. 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Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4452-9320","authenticated-orcid":false,"given":"Steven","family":"Grant","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine Virginia Commonwealth University  Richmond Virginia USA"},{"name":"Massey Cancer Center Virginia Commonwealth University  Richmond Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"3","article-title":"Epidemiology, staging, and management of multiple myeloma","volume":"9","author":"Padala SA","year":"2021","journal-title":"Med Sci 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