{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:59:21Z","timestamp":1791993561993,"version":"4.4.0"},"reference-count":48,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T00:00:00Z","timestamp":1606608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1C1B2003618"],"award-info":[{"award-number":["NRF-2017R1C1B2003618"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["HI16C1559"],"award-info":[{"award-number":["HI16C1559"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4\/6) inhibitors are a highly effective therapy for HR-positive\/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4\/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4\/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4\/6 inhibitor.<\/jats:p>","DOI":"10.3390\/cancers12123566","type":"journal-article","created":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T21:55:31Z","timestamp":1606686931000},"page":"3566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Combined CDK2 and CDK4\/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2144-0577","authenticated-orcid":false,"given":"Kamal","family":"Pandey","sequence":"first","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"},{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2146-6996","authenticated-orcid":false,"given":"Nahee","family":"Park","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Soon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Hur","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"},{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Bin","family":"Cho","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minsil","family":"Kang","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Jung","family":"An","sequence":"additional","affiliation":[{"name":"Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sewha","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"},{"name":"Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7943-974X","authenticated-orcid":false,"given":"Yong Wha","family":"Moon","sequence":"additional","affiliation":[{"name":"Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13488, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2147\/BCTT.S176070","article-title":"Epidemiological characteristics of and risk factors for breast cancer in the world","volume":"11","author":"Momenimovahed","year":"2019","journal-title":"Breast Cancer Targets Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nrclinonc.2015.99","article-title":"Challenges in the management of advanced, ER-positive, HER2-negative breast cancer","volume":"12","author":"Hart","year":"2015","journal-title":"Nat. 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