{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:35:44Z","timestamp":1777890944871,"version":"3.51.4"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100011719","name":"Bone Cancer Research Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011719","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Osteosarcoma (OS) is the most common primary malignant bone tumor. Although the introduction of chemotherapy has improved the survival rate of OS patients, chemoresistance remains a major clinical problem underlying poor survival outcome. This study investigated the role of autophagy in OS chemoresistance and identified ATR as a novel upstream regulator linking DNA damage signaling, autophagy, and chemoresistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Elevated levels of autophagy were found in advanced grade and stage OS tumors, and higher autophagy levels were shown to be associated with poorer OS disease outcome. Chemotherapy significantly increased autophagy levels in HOS\u2010143B cells, while autophagy inhibition by autophagy\u2010related gene 7 knockout (\n                      <jats:italic>ATG7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>)<\/jats:italic>\n                      significantly enhanced cisplatin (CIS) sensitivity in HOS\u2010143B cells. A kinase screen revealed a reduction in the phosphorylation of p53 (S15) in\n                      <jats:italic>ATG7<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      HOS\u2010143B cells. ATR phosphorylates p53 at S15 responsible for DNA Damage Response (DDR), and ATR inhibition increased CIS sensitivity of HOS\u2010143B cells via apoptosis. Subsequent analysis verified that ATR inhibition decreased phosphorylation of p53 at S15 and blocked autophagy in CIS\u2010treated HOS\u2010143B cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings highlight ATR inhibition as a unique therapeutic strategy that simultaneously disrupts DDR signaling and autophagy, thereby enhancing CIS sensitivity. Targeting ATR could reduce the required CIS dosage, limit treatment\u2010associated toxicity, and ultimately improve survival and clinical outcomes for OS patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71658","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:47:37Z","timestamp":1772970457000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of Autophagy Reveals\n                    <scp>ATR<\/scp>\n                    Protein Kinase as a Key Mediator of Cisplatin Sensitivity in Osteosarcoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Janice S.","family":"Pereira","sequence":"first","affiliation":[{"name":"Department of Natural Sciences, Faculty of Science &amp; Technology Middlesex University  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Faculty of Science &amp; Technology Middlesex University  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aine","family":"Pears","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Faculty of Science &amp; Technology Middlesex University  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beata","family":"Burczynska","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Faculty of Science &amp; Technology Middlesex University  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7892-951X","authenticated-orcid":false,"given":"Britta","family":"Stordal","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Faculty of Science &amp; Technology Middlesex University  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott J.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences Royal Veterinary College  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1974-0319","authenticated-orcid":false,"given":"Helen C.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Faculty of Science &amp; Technology Middlesex University  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1051\/sicotj\/2017028"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20102\u20106"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4895"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.09.003"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-3181-0"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2014.02.002"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2013.11.006"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040683"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186885"},{"key":"e_1_2_12_11_1","first-page":"1","article-title":"Autophagy Inhibits Chemotherapy\u2010Induced Apoptosis Through Downregulating Bad and Bim in Hepatocellular Carcinoma Cells","volume":"4","author":"Zhou Y.","year":"2014","journal-title":"Scientific Reports"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102043"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.350"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2010.07.003"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3262"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109415"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.422071"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.343"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018691"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers3022630"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-015-0138-4"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201002108"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.3791\/51046"},{"key":"e_1_2_12_24_1","first-page":"362","article-title":"Autophagy Regulation in Cancer Development and Therapy","volume":"1","author":"White E. 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