Evidence map›Paper›PMID 42518285›Full record

ArticleThe Journal of clinical investigation2026

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

Sahezeel Awadia, Elizabeth K Ziemke, Nicole M Curnutt, Emily Kirk, Julianne Thomas, Anna Zimmerman, Maya J Mileski, Sundaresh Ram, Reine Abou Zeidane, Craig Galban and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Sahezeel AwadiaDepartment of Radiation Oncology and.
Elizabeth K ZiemkeDepartment of Radiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Nicole M CurnuttDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Emily KirkDepartment of Radiation Oncology and.
Julianne ThomasDepartment of Radiation Oncology and.
Anna ZimmermanDepartment of Radiation Oncology and.
Maya J MileskiDepartment of Radiation Oncology and.
Sundaresh RamDepartment of Radiology and Imaging Sciences, Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia, USA.
Reine Abou ZeidaneDepartment of Radiation Oncology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.
Craig GalbanDepartment of Radiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Christina M WooDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Corey W SpeersDepartment of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Judith Sebolt-LeopoldDepartment of Radiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Alnawaz RehemtullaDepartment of Radiation Oncology and.

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Eric R. Fearon · 1988 to 2026
$178.2M
dod HT94252310210dod HT94252310263NCI NIH HHS P30 CA046592
6 · The paper itself

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.

Indexed as

Breast NeoplasmsCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Drug Resistance, NeoplasmFas-Associated Death Domain ProteinNeoplasm ProteinsProtein Kinase InhibitorsAnimalsCell Line, TumorFemaleHumansMicePhosphorylationXenograft Model Antitumor AssaysCDK4 protein, humanCDK6 protein, humanCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Fas-Associated Death Domain ProteinNeoplasm ProteinsProtein Kinase InhibitorsBreast cancerCell biologyCell cycleOncologyTherapeutics

Identifiers

PMID42518285
PMCPMC13574148

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.