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However, most patients eventually develop resistance and discontinue treatment, and there is currently no consensus on effective second-line strategies. Using preclinical HR\n                    <jats:sup>+<\/jats:sup>\n                    human breast cancer models with acquired resistance to CDK4\/6i, we demonstrate that maintaining CDK4\/6i therapy, either alone or combined with CDK2 inhibitors (CDK2i), slows the growth of resistant tumors by prolonging G1 progression. Mechanistically, sustained CDK4\/6 blockade in drug-resistant cells reduces E2F transcription and delays G1\/S via a noncanonical, posttranslational regulation of retinoblastoma protein (Rb). Durable suppression of both CDK2 activity and growth of drug-resistant cells requires co-administration of CDK2i with CDK4\/6i. Moreover, cyclin E overexpression drives resistance to the combination of CDK4\/6i and CDK2i. These findings elucidate how continued CDK4\/6 blockade constrains resistant tumors and support clinical strategies that maintain CDK4\/6i while selectively incorporating CDK2i to overcome resistance.\n                  <\/jats:p>","DOI":"10.7554\/elife.104545","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T19:25:06Z","timestamp":1738005906000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104545","source":"Crossref","is-referenced-by-count":2,"title":["Therapeutic benefits of maintaining CDK4\/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1580-4477","authenticated-orcid":true,"given":"Jessica","family":"Armand","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01esghr10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical 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