{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,11]],"date-time":"2026-01-11T12:06:30Z","timestamp":1768133190638,"version":"3.49.0"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K16044"],"award-info":[{"award-number":["20K16044"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K15340"],"award-info":[{"award-number":["22K15340"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the treatment of chronic myeloid leukemia (CML), resistance to BCR\u2010ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR\u2010ABL inhibitor asciminib and conventional BCR\u2010ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib\u2010resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST\u20108 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA\u2010seq and real\u2010time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR\u2010ABL inhibitors may improve the therapeutic efficacy of conventional BCR\u2010ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross\u2010resistance between BCR\u2010ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.<\/jats:p>","DOI":"10.1002\/prp2.1214","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T14:30:04Z","timestamp":1718980204000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Asciminib, a novel allosteric inhibitor of <scp>BCR\u2010ABL1<\/scp>, shows synergistic effects when used in combination with imatinib with or without drug resistance"],"prefix":"10.1002","volume":"12","author":[{"given":"Naoki","family":"Okamoto","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics Tokushima University Graduate School of Biomedical Sciences  Tokushima Japan"},{"name":"Department of Pharmacy Tokushima University Hospital  Tokushima 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