{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:41:20Z","timestamp":1784137280046,"version":"3.55.0"},"reference-count":54,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,4,11]],"date-time":"2017-04-11T00:00:00Z","timestamp":1491868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["606549"],"award-info":[{"award-number":["606549"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000951","name":"Cancer Council Victoria","doi-asserted-by":"publisher","award":["545969"],"award-info":[{"award-number":["545969"]}],"id":[{"id":"10.13039\/501100000951","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001026","name":"National Breast Cancer Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2017,5]]},"abstract":"\n Heat shock protein 90 (\n HSP<\/jats:styled-content>\n 90) regulates multiple signalling pathways critical for tumour growth. As such,\n HSP<\/jats:styled-content>\n 90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of\n de\u00a0novo<\/jats:italic>\n or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the\n HSP<\/jats:styled-content>\n 90 inhibitor 17\u2010allylamino\u201017\u2010demethoxygeldanamycin (17\u2010\n AAG<\/jats:styled-content>\n ). The resultant resistant cell lines maintained their respective levels of resistance (7\u2013240\u00d7) in the absence of 17\u2010\n AAG<\/jats:styled-content>\n and were also cross\u2010resistant with other benzoquinone ansamycin\n HSP<\/jats:styled-content>\n 90 inhibitors. Expression of members of the histone deacetylase family (\n HDAC<\/jats:styled-content>\n 1, 5, 6) was altered in the resistant cells. To determine whether\n HDAC<\/jats:styled-content>\n activity contributed to resistance, pan\u2010\n HDAC<\/jats:styled-content>\n inhibitors (\n TSA<\/jats:styled-content>\n and\n LBH<\/jats:styled-content>\n 589) and the class\n II HDAC<\/jats:styled-content>\n \u2010specific inhibitor\n SNDX<\/jats:styled-content>\n 275 were found to resensitize resistant cells towards 17\u2010\n AAG<\/jats:styled-content>\n and 17\u2010dimethylaminoethylamino\u201017\u2010demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross\u2010resistant towards structurally distinct\n HSP<\/jats:styled-content>\n 90 inhibitors such as radicicol and the second\u2010generation\n HSP<\/jats:styled-content>\n 90 inhibitors\n CCT<\/jats:styled-content>\n 018159,\n VER<\/jats:styled-content>\n 50589 and\n AUY<\/jats:styled-content>\n 922.\n HDAC<\/jats:styled-content>\n inhibition also resensitized resistant cells towards these classes of\n HSP<\/jats:styled-content>\n 90 inhibitors. In conclusion, we report that prolonged 17\u2010\n AAG<\/jats:styled-content>\n treatment results in acquired resistance of cancer cells towards not just 17\u2010\n AAG<\/jats:styled-content>\n but also to a spectrum of structurally distinct\n HSP<\/jats:styled-content>\n 90 inhibitors. This acquired resistance can be inhibited using clinically relevant\n HDAC<\/jats:styled-content>\n inhibitors. This work supports the potential benefit of using\n HSP<\/jats:styled-content>\n 90 and\n HDAC<\/jats:styled-content>\n inhibitors in combination within the clinical setting.\n <\/jats:p>","DOI":"10.1002\/1878-0261.12054","type":"journal-article","created":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T10:12:50Z","timestamp":1489745570000},"page":"567-583","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Histone deacetylase activity mediates acquired resistance towards structurally diverse\n HSP<\/scp>\n 90 inhibitors"],"prefix":"10.1002","volume":"11","author":[{"given":"Ryan C.","family":"Chai","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia"},{"name":"Bone Division Garvan Institute of Medical Research Darlinghurst NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Vieusseux","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia"},{"name":"Department of Radiation Oncology Centre for Life Sciences Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia"},{"name":"College of Health and Biomedicine Victoria University Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Kouspou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara L.","family":"Britt","sequence":"additional","affiliation":[{"name":"Peter MacCallum Cancer Centre Melbourne Vic. Australia"},{"name":"The Sir Peter MacCallum Department of Oncology University of Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8244-1023","authenticated-orcid":false,"given":"John T.","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Monash University Clayton Vic. Australia"},{"name":"College of Health and Biomedicine Victoria University Melbourne Vic. Australia"},{"name":"Australian Institute for Musculoskeletal Science (AIMSS) Victoria University and University of Melbourne Vic. Australia"},{"name":"Department of Medicine Melbourne Medical School\u2010Western Precinct The University of Melbourne St Albans Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,4,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208955"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm701018h"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-15-0234"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clcc.2014.09.001"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1528"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.991"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds275"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5256"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3131"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-09-3413"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.10.013"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1799"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0221"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-3268"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.10.008"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.7328"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1543-z"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.04.021"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2014.08.001"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.371120"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568009033481822"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1629"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5175"},{"key":"e_1_2_8_25_1","first-page":"308","article-title":"Comparison 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