Targeting casein kinase 1α-mediated FADD phosphorylation restores sensitivity in select CDK4/6 inhibitor-resistant breast cancer models

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Abstract
Resistance to CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy presents a major barrier to improving outcomes in ER + breast cancer. 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 CK1α degrader DEG-77, or PI3K inhibition, restored CDK4/6i sensitivity in resistant cells. In CDK4/6i-refractory xenografts, CK1α 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 CK1α-mediated FADD phosphorylation as a targetable resistance mechanism in a subset of CDK4/6i-resistant ER + /HER2 – breast cancer.
Funding Information
  • U.S. Department of War (HT94252310210)
  • U.S. Department of War (HT94252310263)
  • National Cancer Institute (CA046592)

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