{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:23:01Z","timestamp":1777375381283,"version":"3.51.4"},"reference-count":254,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T00:00:00Z","timestamp":1696204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)\/Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior (MCTES) through Fundos do Or\u00e7amento de Estado","award":["PTDC\/MED-ONC\/28636\/2017"],"award-info":[{"award-number":["PTDC\/MED-ONC\/28636\/2017"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)\/Minist\u00e9rio da Ci\u00eancia, Tecnologia e Ensino Superior (MCTES) through Fundos do Or\u00e7amento de Estado","award":["SFRH\/BD\/139178\/2018"],"award-info":[{"award-number":["SFRH\/BD\/139178\/2018"]}]},{"name":"FCT","award":["PTDC\/MED-ONC\/28636\/2017"],"award-info":[{"award-number":["PTDC\/MED-ONC\/28636\/2017"]}]},{"name":"FCT","award":["SFRH\/BD\/139178\/2018"],"award-info":[{"award-number":["SFRH\/BD\/139178\/2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The approval of cyclin-dependent kinase 4 and 6 inhibitors (CDK4\/6i) in combination with endocrine therapy (ET) has remarkably improved the survival outcomes of patients with advanced hormone receptor-positive (HR+) breast cancer (BC), becoming the new standard of care treatment in these patients. Despite the efficacy of this therapeutic combination, intrinsic and acquired resistance inevitably occurs and represents a major clinical challenge. Several mechanisms associated with resistance to CDK4\/6i have been identified, including both cell cycle-related and cell cycle-nonspecific mechanisms. This review discusses new insights underlying the mechanisms of action of CDK4\/6i, which are more far-reaching than initially thought, and the currently available evidence of the mechanisms of resistance to CDK4\/6i in BC. Finally, it highlights possible treatment strategies to improve CDK4\/6i efficacy, summarizing the most relevant clinical data on novel combination therapies involving CDK4\/6i.<\/jats:p>","DOI":"10.3390\/cancers15194835","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T11:56:49Z","timestamp":1696247809000},"page":"4835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Evolving Pathways of the Efficacy of and Resistance to CDK4\/6 Inhibitors in Breast Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-0821","authenticated-orcid":false,"given":"In\u00eas","family":"Gomes","sequence":"first","affiliation":[{"name":"Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]},{"given":"Catarina","family":"Abreu","sequence":"additional","affiliation":[{"name":"Oncology Division, Hospital de Santa Maria\u2014Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-7318","authenticated-orcid":false,"given":"Luis","family":"Costa","sequence":"additional","affiliation":[{"name":"Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisbon, Portugal"},{"name":"Oncology Division, Hospital de Santa Maria\u2014Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6917-4477","authenticated-orcid":false,"given":"Sandra","family":"Casimiro","sequence":"additional","affiliation":[{"name":"Luis Costa Lab, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, 1649-028 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/BF00268085","article-title":"Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe","volume":"146","author":"Nurse","year":"1976","journal-title":"Mol. 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