{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T18:49:06Z","timestamp":1773686946607,"version":"3.50.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"3","funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["113\u20132320-B-182-021"],"award-info":[{"award-number":["113\u20132320-B-182-021"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["114\u20132320-B-182-021"],"award-info":[{"award-number":["114\u20132320-B-182-021"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010101","name":"Taichung Veterans General Hospital","doi-asserted-by":"publisher","award":["TCVGH-T1137809"],"award-info":[{"award-number":["TCVGH-T1137809"]}],"id":[{"id":"10.13039\/501100010101","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["BMRPC17"],"award-info":[{"award-number":["BMRPC17"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPD1M0582"],"award-info":[{"award-number":["CMRPD1M0582"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPD1P0151"],"award-info":[{"award-number":["CMRPD1P0151"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research","award":["ZIA BC010030"],"award-info":[{"award-number":["ZIA BC010030"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Chemotherapy remains central to cancer management, but its effectiveness is often limited by multidrug resistance (MDR), largely mediated by the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein; P-gp). As no clinically approved inhibitors are available to overcome ABCB1-mediated MDR, this study aimed to evaluate befotertinib (D-0316), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved by the National Medical Products Administration, for its potential to modulate ABCB1 activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cytotoxicity and apoptosis assays were used to assess chemosensitization in multidrug-resistant cancer cells. Drug efflux inhibition was examined, while vanadate-sensitive ATPase activity and molecular docking analyses were performed to characterize interactions between befotertinib and ABCB1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>Befotertinib significantly enhanced anticancer drug-induced apoptosis and resensitized resistant cells in a concentration-dependent manner. It inhibited ABCB1-mediated efflux, stimulating ATPase activity and demonstrating direct binding to key residues within the ABCB1 substrate-binding pocket.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results identify befotertinib as a functional inhibitor of ABCB1 with the capacity to reverse MDR. The findings support its potential as a repurposed agent for combination therapy in tumors with high ABCB1 expression, offering a practical strategy to enhance chemotherapy efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jpp\/rgag020","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T12:24:15Z","timestamp":1771849455000},"source":"Crossref","is-referenced-by-count":0,"title":["Befotertinib restored chemosensitivity to multidrug-resistant cancer cells by inhibiting the drug efflux activity of ABCB1"],"prefix":"10.1093","volume":"78","author":[{"given":"Yen-Ching","family":"Li","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University , No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang-Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University , No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Shan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Tunghai University , No. 1727, Sec. 4, Taiwan Boulevard, Xitun Dist., Taichung 40704 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tai-Ho","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital , No. 199, Dunhua N. Rd., Songshan Dist., Taipei City 105406 ,","place":["Taiwan"]},{"name":"Department of Medicine, College of Medicine, Chang Gung University , No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302 ,","place":["Taiwan"]},{"name":"Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital , No. 222, Maijin Rd., Anle Dist., Keelung 20401 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh V","family":"Ambudkar","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-3361","authenticated-orcid":false,"given":"Chung-Pu","family":"Wu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University , No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302 ,","place":["Taiwan"]},{"name":"Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital , No. 199, Dunhua N. Rd., Songshan Dist., Taipei City 105406 ,","place":["Taiwan"]},{"name":"Department of Physiology and Pharmacology, College of Medicine, Chang Gung University , No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302 ,","place":["Taiwan"]},{"name":"Molecular Medicine Research Center, College of Medicine, Chang Gung University , No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302 ,","place":["Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"2026031613512140000_ref1","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/s41568-023-00612-3","article-title":"Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters","volume":"23","author":"Sajid","year":"2023","journal-title":"Nat Rev Cancer"},{"key":"2026031613512140000_ref2","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","article-title":"Revisiting the role of ABC transporters in multidrug-resistant cancer","volume":"18","author":"Robey","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"2026031613512140000_ref3","doi-asserted-by":"publisher","first-page":"4236","DOI":"10.3390\/cancers15174236","article-title":"Genetics of ABCB1 in cancer","volume":"15","author":"Skinner","year":"2023","journal-title":"Cancers."},{"key":"2026031613512140000_ref4","doi-asserted-by":"crossref","first-page":"100681","DOI":"10.1016\/j.drup.2020.100681","article-title":"Medicinal chemistry strategies to discover P-glycoprotein inhibitors: an update","volume":"49","author":"Dong","year":"2020","journal-title":"Drug Resist Updat"},{"key":"2026031613512140000_ref5","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/0005-2736(76)90160-7","article-title":"A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants","volume":"455","author":"Juliano","year":"1976","journal-title":"Biochim Biophys Acta"},{"key":"2026031613512140000_ref6","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1080\/13543776.2019.1618273","article-title":"An updated patent review on P-glycoprotein inhibitors (2011-2018)","volume":"29","author":"Leopoldo","year":"2019","journal-title":"Expert opinion on therapeutic patents"},{"key":"2026031613512140000_ref7","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.ejca.2003.09.036","article-title":"Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy","volume":"40","author":"Walker","year":"2004","journal-title":"Eur J Cancer"},{"key":"2026031613512140000_ref8","doi-asserted-by":"crossref","first-page":"101011","DOI":"10.1016\/j.drup.2023.101011","article-title":"Perspectives on drug repurposing to overcome cancer multidrug resistance mediated by ABCB1 and ABCG2","volume":"71","author":"Wu","year":"2023","journal-title":"Drug Resist Updat"},{"key":"2026031613512140000_ref9","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1016\/j.jtho.2022.06.002","article-title":"Efficacy and safety of Befotertinib (D-0316) in patients with EGFR T790M-mutated NSCLC that had progressed after prior EGFR tyrosine kinase inhibitor therapy: a phase 2, Multicenter, single-arm, open-label study","volume":"17","author":"Lu","year":"2022","journal-title":"Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer"},{"key":"2026031613512140000_ref10","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1093\/oncolo\/oyab007","article-title":"Phase I trial of a third generation EGFR mutant-selective inhibitor (D-0316) in patients with advanced non-small cell lung cancer","volume":"27","author":"Jian","year":"2022","journal-title":"Oncologist."},{"key":"2026031613512140000_ref11","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/nrclinonc.2014.104","article-title":"Acquired resistance to TKIs in solid tumours: learning from lung cancer","volume":"11","author":"Camidge","year":"2014","journal-title":"Nat Rev Clin Oncol"},{"key":"2026031613512140000_ref12","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1007\/s40265-023-01946-w","article-title":"Befotertinib: First approval","volume":"83","author":"Blair","year":"2023","journal-title":"Drugs."},{"key":"2026031613512140000_ref13","first-page":"12","article-title":"Befotertinib: one more drug targeting EGFR-the more may be the merrier. 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