{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T04:28:31Z","timestamp":1777955311982,"version":"3.51.4"},"reference-count":312,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04539\/2020"],"award-info":[{"award-number":["UIDP\/04539\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PI18\/00591"],"award-info":[{"award-number":["PI18\/00591"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients\u2019 compliance\/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.<\/jats:p>","DOI":"10.3390\/cancers13194820","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T01:59:47Z","timestamp":1632707987000},"page":"4820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":168,"title":["Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia\u2014From Molecular Mechanisms to Clinical Relevance"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2599-6433","authenticated-orcid":false,"given":"Raquel","family":"Alves","sequence":"first","affiliation":[{"name":"Laboratory of Oncobiology and Hematology, University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Group of Environment Genetics and Oncobiology (CIMAGO), Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-4802","authenticated-orcid":false,"given":"Ana Cristina","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology, University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Group of Environment Genetics and Oncobiology (CIMAGO), Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1970-7375","authenticated-orcid":false,"given":"Sergio","family":"Rutella","sequence":"additional","affiliation":[{"name":"John van Geest Cancer Research Centre, Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK"}]},{"given":"Ant\u00f3nio M.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Hospital da Luz Lisboa, 1500-650 Lisbon, Portugal"},{"name":"Faculdade de Medicina, Universidade Cat\u00f3lica Portuguesa, 2635-631 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-9946","authenticated-orcid":false,"given":"Javier","family":"De Las Rivas","sequence":"additional","affiliation":[{"name":"Cancer Research Center (CiC-IBMCC, CSIC\/USAL\/IBSAL, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), University of Salamanca (USAL) and Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL)), 37007 Salamanca, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6179-2772","authenticated-orcid":false,"given":"Ioannis P.","family":"Trougakos","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, 15784 Athens, Greece"},{"name":"Department of Life Sciences, European University Cyprus, 2404 Nicosia, Cyprus"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4142-4841","authenticated-orcid":false,"given":"Ana Bela","family":"Sarmento Ribeiro","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology, University Clinic of Hematology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Group of Environment Genetics and Oncobiology (CIMAGO), Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"},{"name":"Hematology Service, Centro Hospitalar e Universit\u00e1rio de Coimbra (CHUC), 3000-061 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Baykal-K\u00f6se, S., Acikgoz, E., Yavuz, A.S., G\u00f6n\u00fcl Geyik, \u00d6., Ate\u015f, H., Sezerman, O.U., \u00d6zsan, G.H., and Y\u00fcce, Z. 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