{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:15:32Z","timestamp":1783008932978,"version":"3.54.5"},"reference-count":32,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":69,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 CA223220"],"award-info":[{"award-number":["R01 CA223220"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["UG1 CA233259"],"award-info":[{"award-number":["UG1 CA233259"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Emory University","award":["Emory Winship Cancer Institute lung cancer research pilot funds"],"award-info":[{"award-number":["Emory Winship Cancer Institute lung cancer research pilot funds"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,15]]},"abstract":"<jats:p>\n                    Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non\u2013small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo II\u03b1 levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo II\u03b1. Increased Topo II\u03b1 levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic\n                    <jats:italic>TOP2A<\/jats:italic>\n                    gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of\n                    <jats:italic>TOP2A<\/jats:italic>\n                    in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo II\u03b1 inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.\n                  <\/jats:p>","DOI":"10.1172\/jci172716","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T12:00:20Z","timestamp":1709812820000},"source":"Crossref","is-referenced-by-count":30,"title":["DNA topoisomerase II inhibition potentiates osimertinib\u2019s therapeutic efficacy in EGFR-mutant non\u2013small cell lung cancer models"],"prefix":"10.1172","volume":"134","author":[{"given":"Zhen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin 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