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Adv."],"published-print":{"date-parts":[[2026,10,2]]},"abstract":"<jats:p>Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor\u2013positive (HR+) subtype. Cyclin-dependent kinase 4\/6 (CDK4\/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases, no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4\/6 inhibitors using breast cancer patient\u2013derived models and tumors. We identified an unexpected, noncanonical nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4\/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4\/6 inhibitor\u2013resistant HR+ breast cancer.<\/jats:p>","DOI":"10.1126\/sciadv.aef1145","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:58:26Z","timestamp":1790791106000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A noncanonical function of the tyrosine degradation enzyme FAH drives CDK4\/6 inhibitor resistance in breast cancer"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5932-0146","authenticated-orcid":true,"given":"Jenny","family":"H\u00f6gstr\u00f6m","sequence":"first","affiliation":[{"name":"Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 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A. Cianfrocco M. Wong-Barnum C. Youn R. Wagner A. Leschziner \u201cCOSMIC2: A science gateway for cryo-electron microscopy structure determination \u201d in Practice and Experience in Advanced Research Computing 2017: Sustainability Success and Impact [New Orleans (LA): Association for Computing Machinery 2017] pp. 1\u20135.","DOI":"10.1145\/3093338.3093390"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506583102"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1339.047"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1042"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aef1145","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:58:43Z","timestamp":1790791123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aef1145"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":59,"journal-issue":{"issue":"40","published-print":{"date-parts":[[2026,10,2]]}},"alternative-id":["10.1126\/sciadv.aef1145"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aef1145","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,2]]},"assertion":[{"value":"2026-01-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaef1145"}}