{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:15:24Z","timestamp":1789964124550,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2016,6,21]],"date-time":"2016-06-21T00:00:00Z","timestamp":1466467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Sugita Genpaku Memorial Obama Municipal Hospital","award":["J110000964"],"award-info":[{"award-number":["J110000964"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2016,7]]},"abstract":"The major mechanism of imatinib (IM<\/jats:styled-content>) resistance of CML<\/jats:styled-content> is the reactivation of ABL<\/jats:styled-content> kinase either through BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content><\/jats:italic> gene amplification or mutation. We investigated the cytotoxicity of a pan\u2010ABL<\/jats:styled-content> tyrosine kinase inhibitor, ponatinib, and a pan\u2010histone deacetylase inhibitor, panobinostat, against IM<\/jats:styled-content>\u2010resistant CML<\/jats:styled-content> cells in\u00a0vitro<\/jats:italic>. Two different IM<\/jats:styled-content>\u2010resistant cell lines, K562\/IM<\/jats:styled-content>\u2010R1 and Ba\/F3\/T315I were evaluated in comparison with their respective, parental cell lines, K562 and Ba\/F3. K562\/IM<\/jats:styled-content>\u2010R1 overexpressed BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content> due to gene amplification. Ba\/F3\/T315I was transfected with a BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content><\/jats:italic> gene encoding T315I\u2010mutated BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content>. Ponatinib inhibited the growth of both K562\/IM<\/jats:styled-content>\u2010R1 and Ba\/F3\/T315I as potently as it inhibited their parental cells with an IC<\/jats:styled-content>50<\/jats:sub> of 2\u201330\u00a0nM<\/jats:styled-content>. Panobinostat also similarly inhibited the growth of all of the cell lines with an IC<\/jats:styled-content>50<\/jats:sub> of 40\u201351\u00a0nM<\/jats:styled-content>. This was accompanied by reduced histone deacetylase activity, induced histone H3 acetylation, and an increased protein level of heat shock protein 70, which suggested disruption of heat shock protein 90 chaperone function for BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content> and its degradation. Importantly, the combination of ponatinib with panobinostat showed synergistic growth inhibition and induced a higher level of apoptosis than the sum of the apoptosis induced by each agent alone in all of the cell lines. Ponatinib inhibited phosphorylation not only of BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content> but also of downstream signal transducer and activator of transcription 5, protein kinase B, and ERK<\/jats:styled-content>1\/2 in both K562\/IM<\/jats:styled-content>\u2010R1 and Ba\/F3\/T315I, and the addition of panobinostat to ponatinib further inhibited these phosphorylations. In conclusion, panobinostat enhanced the cytotoxicity of ponatinib towards IM<\/jats:styled-content>\u2010resistant CML<\/jats:styled-content> cells including those with T315I\u2010mutated BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/cas.12965","type":"journal-article","created":{"date-parts":[[2016,5,11]],"date-time":"2016-05-11T18:10:15Z","timestamp":1462990215000},"page":"1029-1038","source":"Crossref","is-referenced-by-count":34,"title":["Combination of panobinostat with ponatinib synergistically overcomes imatinib\u2010resistant CML<\/scp> cells"],"prefix":"10.1111","volume":"107","author":[{"given":"Yasufumi","family":"Matsuda","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology Faculty of Medical Sciences University of Fukui Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Hematology and 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