{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:03:10Z","timestamp":1790244190602,"version":"4.1.0"},"reference-count":75,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Treatment of metastatic breast cancer with CDK4\/6 inhibitors in combination with hormone ablation is the current first-line standard of care for this indication, and the therapeutic activity of these inhibitors has been demonstrated in various tumor entities. However, the efficacy of CDK4\/6 inhibitor monotherapy is limited and requires combination with suitable additional inhibitors. Delineating the molecular pathways underlying treatment response may provide a rationale for personalized combination therapies that target deregulated pathways upstream of the core signature of response. We applied a comprehensive cross-omics approach to identify a conserved molecular response to CDK4\/6 inhibition. Integration of transcriptomic, proteomic, and functional genomic data across multiple cancer models enabled us to refine a previously proposed multi-step model of response to the CDK4\/6 inhibitor palbociclib. Initiation of cell-cycle arrest and inhibition of DNA replication is followed by activation of signaling events that suppress mitotic transcriptional programs. The identified panel of highly conserved candidate biomarkers warrants future experimental and clinical validation.<\/jats:p>","DOI":"10.3390\/ijms27198507","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:07:54Z","timestamp":1790240874000},"page":"8507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of a Conserved Temporal Molecular Response Signature to CDK4\/6 Inhibition Through Multi-Omics Integration Across Cancer Cell Lines"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8109-3188","authenticated-orcid":false,"given":"Anna C.","family":"Hogger","sequence":"first","affiliation":[{"name":"Department of Urology, TUM Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Stra\u00dfe 22, 81675 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Urology, TUM Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Stra\u00dfe 22, 81675 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Klaus","family":"Mantwill","sequence":"additional","affiliation":[{"name":"Department of Urology, TUM Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Stra\u00dfe 22, 81675 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Nadine","family":"Gaisa","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital RWTH Aachen, RWTH Aachen University, Pauwelsstra\u00dfe 30, 52074 Aachen, Germany"},{"name":"Institute of Pathology, University Hospital Ulm, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"J\u00fcrgen E.","family":"Gschwend","sequence":"additional","affiliation":[{"name":"Department of Urology, TUM Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Stra\u00dfe 22, 81675 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Roman","family":"Nawroth","sequence":"additional","affiliation":[{"name":"Department of Urology, TUM Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Stra\u00dfe 22, 81675 M\u00fcnchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41523-023-00520-7","article-title":"The dilemma of selecting a first line CDK4\/6 inhibitor for hormone receptor-positive\/HER2-negative metastatic breast cancer","volume":"9","author":"Grinshpun","year":"2023","journal-title":"NPJ Breast Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"eabc1495","DOI":"10.1126\/science.abc1495","article-title":"CDK4 and CDK6 kinases: From basic science to cancer therapy","volume":"375","author":"Fassl","year":"2022","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2100211","DOI":"10.1200\/PO.21.00211","article-title":"Clinical Utility of CDK4\/6 Inhibitors in Sarcoma: Successes and Future Challenges","volume":"6","author":"Hsu","year":"2022","journal-title":"JCO Precis. 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