Related Experiment Video

Updated: Aug 5, 2026

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
12:26

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

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

Sahezeel Awadia1, Elizabeth K Ziemke2, Nicole M Curnutt3

  • 1Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, United States of America.

The Journal of Clinical Investigation
|July 28, 2026
PubMed

Insights

A novel mechanism of resistance to CDK4/6 inhibitors in ER+ breast cancer involves FADD phosphorylation. Targeting this pathway with CK1α degraders may restore treatment sensitivity and improve outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Endocrine therapy resistance limits efficacy in ER+ breast cancer.
  • CDK4/6 inhibitors (CDK4/6i) are standard treatment but resistance develops.
  • Identifying resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To elucidate a novel mechanism of CDK4/6i resistance in ER+ breast cancer.
  • To investigate the role of FADD phosphorylation in mediating resistance.
  • To evaluate therapeutic strategies targeting this resistance pathway.

Main Methods:

  • Utilized cell and xenograft models of ER+ breast cancer.
  • Investigated FADD phosphorylation at Ser194 (phospho-FADD) and its interaction with APC/C-Cdh1.
  • Assessed PI3K pathway activation and its link to phospho-FADD.
  • Analyzed patient biopsies for phospho-FADD and pAKT levels.
  • Tested CK1α degrader DEG-77 and PI3K inhibitors in combination with CDK4/6i.

Main Results:

  • Identified phospho-FADD as a mediator of CDK4/6i resistance by inhibiting APC/C-Cdh1.
  • Observed a CDK4/6-independent pathway associated with PI3K hyperactivation.
  • Found increased phospho-FADD and pAKT in 73% of post-treatment recurrent patient biopsies.
  • Demonstrated that inhibiting FADD phosphorylation or PI3K restored CDK4/6i sensitivity.
  • Achieved profound tumor regressions and improved survival in xenografts using combined CK1α degradation and CDK4/6i therapy.

Conclusions:

  • CK1α-mediated FADD phosphorylation is a targetable resistance mechanism in CDK4/6i-resistant ER+/HER2- breast cancer.
  • Targeting this pathway offers a potential strategy to overcome resistance and improve treatment efficacy.
  • Combined CK1α degradation and CDK4/6i therapy shows significant promise in preclinical models.
Keywords:
Breast cancerCell biologyCell cycleOncologyTherapeutics

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