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We identified FADD phosphorylation at Ser194 (phospho-FADD) as a mediator of CDK4\/6i resistance in the models examined. Phospho-FADD acted as a pseudosubstrate inhibitor of the APC\/C-Cdh1 complex, promoting G1\/S transition and bypassing the canonical CDK4\/6-Rb-E2F pathway. This CDK4\/6-independent pathway was associated with PI3K hyperactivation. Clinical relevance of this bypass pathway was supported by increased phospho-FADD and pAKT in 73% of paired patient biopsies at posttreatment recurrence, while the remaining cases exhibited high baseline phospho-FADD and pAKT with intrinsic nonresponse. Inhibition of FADD phosphorylation with the CK1\u03b1 degrader DEG-77, or PI3K inhibition, restored CDK4\/6i sensitivity in resistant cells. In CDK4\/6i-refractory xenografts, CK1\u03b1 degradation combined with CDK4\/6i resulted in profound tumor regressions and increased progression-free survival compared with either single agent, including complete tumor regressions in 92% of tumors. These findings support CK1\u03b1-mediated FADD phosphorylation as a targetable resistance mechanism in a subset of CDK4\/6i-resistant ER\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2013<\/jats:sup>\n                    breast cancer.\n                  <\/jats:p>","DOI":"10.1172\/jci199483","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T16:00:16Z","timestamp":1785254416000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting casein kinase 1\u03b1-mediated FADD phosphorylation restores sensitivity in select CDK4\/6 inhibitor-resistant breast cancer models"],"prefix":"10.1172","volume":"136","author":[{"given":"Sahezeel","family":"Awadia","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth K.","family":"Ziemke","sequence":"additional","affiliation":[{"name":"Department of 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