{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:45:23Z","timestamp":1792007123871,"version":"4.4.0"},"reference-count":108,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:p>\n                    Cell-cycle dysregulation is a central driver of breast cancer progression and a major therapeutic vulnerability, particularly in hormone receptor\u2013positive\/human epidermal growth factor receptor 2\u2013negative (HR\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2013<\/jats:sup>\n                    ) disease. The clinical success of cyclin-dependent kinase (CDK) 4\/6 inhibitors combined with endocrine therapy has transformed treatment paradigms and established cell-cycle targeting as a cornerstone of care. However, important challenges remain, including hematologic toxicity, incomplete and largely cytostatic responses, and the near-universal development of resistance. These limitations have highlighted the need for next-generation CDK-directed strategies capable of improving selectivity, extending disease control, and overcoming adaptive escape pathways. This Review examines the evolving landscape of CDK-targeted therapeutics in breast cancer, with particular emphasis on emerging CDK4-selective inhibitors, CDK2-directed approaches, and broader multi-CDK strategies. We discuss the biological rationale underpinning these agents, the mechanisms of resistance that have informed their development, and the clinical opportunities they may create across both advanced and early-stage settings. By refining target specificity and addressing resistance-associated cell-cycle rewiring, next-generation CDK inhibitors may reduce toxicity, enhance treatment durability, and enable more effective combination and sequencing strategies. Collectively, these advances promise to move breast cancer treatment beyond current CDK4\/6 inhibition toward more precise, adaptable, and durable cell-cycle\u2013directed therapy.\n                  <\/jats:p>","DOI":"10.1172\/jci207631","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:54:47Z","timestamp":1792004087000},"source":"Crossref","is-referenced-by-count":0,"title":["Next-generation CDK inhibitors in HR+\/HER2\u2013 breast cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Daria","family":"Seriak","sequence":"first","affiliation":[{"name":"Dana-Farber Cancer Institute at Boston Medical Center, Brighton, Massachusetts, USA."},{"name":"Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Yong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical, School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3331-4095","authenticated-orcid":true,"given":"Geoffrey I.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical, School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Giordano","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical, School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.12.049"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2602"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02080-z"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-20769-5"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02872"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.8.4215"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.2.753"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.14.4773-4784.2001"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07554-2"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.16.7260-7274.2004"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.9.5338"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101103"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2023.2000"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020293"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.03.7689"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-025-14841-2"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17213538"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1177\/1758835918793326"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2025.102980"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1390"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2022.119346"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.116140"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2309261121"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2019.113676"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.023"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-026-01431-5"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104324"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.01.017"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-2428"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.02.006"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2015.1084445"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c02137"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607303"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2026.106063"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.3009"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.08.943"},{"key":"B37","unstructured":"Pfizer. Study of PF-07220060 with letrozole in adults with HR-positive, HER2-negative breast cancer who have not received anticancer treatment for advanced\/metastatic disease. https:\/\/clinicaltrials.gov\/study\/NCT06760637 Updated May 19, 2026. Accessed July 19, 2026"},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2024.103206","article-title":"184MO First-in-human phase I\/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+\/HER2\u2212 metastatic breast cancer (mBC) who progressed on prior CDK4\/6 inhibitors (CDK4\/6i): safety and efficacy update","volume":"9","author":"Yap","year":"2024","journal-title":"ESMO Open"},{"key":"B39","unstructured":"Pfizer. Pfizer Announces Positive Topline Phase 2 Results for Next-Generation CDK4 Inhibitor, Atirmociclib, in Second-Line Metastatic Breast Cancer. https:\/\/www.pfizer.com\/news\/press-release\/press-release-detail\/pfizer-announces-positive-topline-phase-2-results-next Update March 17, 2026. Accessed June 13, 2026"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2026.44.16_suppl.1075"},{"key":"B41","unstructured":"Relay Therapeutics. Relay Therapeutics announces clinical data for zovegalisib plus atirmociclib triplet combination supportive of further development in frontline metastatic breast cancer. https:\/\/ir.relaytx.com\/news-releases\/news-release-details\/relay-therapeutics-announces-clinical-data-zovegalisib-plus\/ Updated April 27, 2026. Accessed June 13, 2026"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.361"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.11.006"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1726"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.379"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.02.023"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-25-1406"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS24-P4-10-06"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS24-P4-10-20"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2026.44.16_suppl.1066"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0728"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-018-0092-4"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.00925"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5290-4"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-026-01519-6"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-23-0496"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56674-4"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0954"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-2360"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adv0415"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(03)00053-9"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(06)00121-7"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01710-07"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1758"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.8.4325"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-022-00311-6"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.104545.3"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-025-00851-7"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2024-5709"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.3010"},{"key":"B71","doi-asserted-by":"crossref","unstructured":"Juric D, et al. CDK2 inhibition exerts RB-independent antitumor activity in CDK4\/6 inhibitor\u2013resistant HR+\/HER2\u2212 breast cancer [published online July 2, 2026]. Cancer Res. https:\/\/doi.org\/10.1158\/0008-5472.can-25-1859","DOI":"10.1158\/0008-5472.CAN-25-1859"},{"issue":"5 suppl","key":"B72","article-title":"Abstract P6-10-07: CDK2 inhibition with BLU-222 in combination with ribociclib demonstrates robust antitumor activity in pre-clinical models of CDK4\/6 inhibitor-na\u00efve and -resistant HR+\/HER2- breast cancer","volume":"83","author":"Brown","year":"2023","journal-title":"Cancer Res"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.1056"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.08.1543"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS24-P4-10-16"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS24-P4-12-29"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.16_suppl.3115"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-67865-4"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2024-4622"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.05.013"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.685"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-2740"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS25-PS2-11-28"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS25-PS1-11-07"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33054"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2019.03.035"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00871"},{"issue":"9 suppl","key":"B89","article-title":"Abstract PO5-05-02: discovery of BTX-9341, a bifunctional degrader of CDK4 and CDK6 for HR+\/HER2- breast cancer","volume":"84","author":"Majeski","year":"2024","journal-title":"Cancer Res"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS25-PS4-06-04"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201901336"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2026.118569"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-023-01146-w"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52966-3"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c02713"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14061554"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6c10277"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2024.114543"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1158\/1557-3265.SABCS25-PS4-04-30"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2505725"},{"key":"B101","unstructured":"US Food Drug Administration. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast Published online May 1, 2026. Accessed August 19, 2026"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1177\/1947601912473308"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.4161\/cc.26355"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(05)00004-3"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1104"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2546"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2975"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40061-y"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/207631\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:54:52Z","timestamp":1792004092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/207631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,15]]},"references-count":108,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2026,10,15]]},"published-print":{"date-parts":[[2026,10,15]]}},"alternative-id":["10.1172\/JCI207631"],"URL":"https:\/\/doi.org\/10.1172\/jci207631","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,15]]},"article-number":"e207631"}}