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CDK1 lies immediately downstream of CDK4\/6 but has not been investigated as a prognostic marker for ER+ disease. Here, we integrate real\u2010time imaging of a novel Cdk1 activity biosensor mouse with clinical cohorts to establish CDK1 as a candidate biomarker of progression and therapeutic sensitivity. Using the MMTV\u2010PyMT;MMTV\u2010Cre;Cdk1\u2010FRET biosensor mouse, we visualized Cdk1 upregulation in situ during the transition to invasive ductal carcinoma (IDC). Clinically, we identified that pCDK1\n                    <jats:sup>T161<\/jats:sup>\n                    is specifically upregulated in IDC, and that pCDK1\n                    <jats:sup>Y15<\/jats:sup>\n                    is prognostic of poor relapse\u2010free survival in stage 1 disease. We further characterized CDK1 activity as part of a dynamic adaptive response to CDK4\/6 inhibition: the CDK1\/cyclin B1 complex was suppressed, then rebounded within 3 days. In the NeoPalAna trial, non\u2010responders incompletely suppressed\n                    <jats:italic>CDK1<\/jats:italic>\n                    . Palbociclib\u2010resistant cells recovered basal CDK1 in vitro, non\u2010responsive tumors exhibited elevated Cdk1 activity in vivo, and\n                    <jats:italic>CDK1<\/jats:italic>\n                    was elevated in CDK4\/6 inhibitor\u2010resistant patient tumors. Together, our findings position CDK1 as a candidate biomarker for poor prognosis in early disease, and an indicator of adaptive responses and resistance to CDK4\/6 inhibition.\n                  <\/jats:p>","DOI":"10.1002\/advs.77920","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:19:07Z","timestamp":1791775147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tracking CDK1 Dynamics With a Novel Biosensor Mouse and Clinical Cohorts to Predict CDK4\/6 Inhibitor Sensitivity in ER+ Breast Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1186-6507","authenticated-orcid":false,"given":"Sarah","family":"Alexandrou","sequence":"first","affiliation":[{"name":"St Vincent's Clinical School, Faculty of Medicine UNSW Sydney  Sydney New South Wales Australia"},{"name":"Garvan Institute of Medical Research  Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5509-6807","authenticated-orcid":false,"given":"Kristine J.","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research  Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Li","family":"Huang","sequence":"additional","affiliation":[{"name":"St Vincent's Clinical School, Faculty of Medicine UNSW Sydney  Sydney New South Wales Australia"},{"name":"SydPath Department of Anatomical Pathology St Vincent's Hospital  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewan K. 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