Faculty Collaboration Database

Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant Persister Cells. FASEB J 2026 Apr 15;40(7):e71746

Date

04/01/2026

Pubmed ID

41920074

DOI

10.1096/fj.202502515RR

Scopus ID

2-s2.0-105034818382 (requires institutional sign-in at Scopus site)

Abstract

Although endocrine therapies prevent recurrence and progression of estrogen receptor alpha (ER)-positive breast cancer, approximately one-third of patients experience recurrent disease that is rarely cured in the advanced/metastatic setting. A subpopulation of endocrine-tolerant breast cancer cells persists as residual disease that confers risk for the eventual emergence of drug resistance. An analysis of persisters that continue to proliferate despite endocrine therapy revealed the activation of pathways related to metabolism and E2F transcription factor signaling. E2F signaling is driven by cyclin-dependent kinases 4 and 6 (CDK4/6), and CDK4/6 inhibitors (CDK4/6i) are used clinically to prevent and manage endocrine resistance. CDK4/6i slowed the cycling of endocrine-tolerant persisters. Analyzing metabolic alterations induced by CDK4/6i, we found that CDK4/6i-tolerant persisters had upregulation of mitochondrial content, mitochondrial membrane potential, respiration, and reactive oxygen species (ROS). Inhibition of mitochondrial complex I further increased ROS levels and enhanced growth inhibition in both endocrine-sensitive and -resistant cell lines and patient-derived xenografts. These findings collectively offer mitochondrial respiration as a therapeutic target in CDK4/6-tolerant persister breast cancer cells to help eradicate residual disease.

Author List

Yang H, Tau S, McCray AD, Roberts AM, Marotti JD, Muller K, Huang Y, Al Mamun M, Aoki K, Demidenko E, Miller TW

Authors

Kazuhiro Aoki PhD, MEd Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Md Al Mamun PhD, BS, MSc Research Scientist II in the Cancer Center department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aminopyridines
Animals
Benzimidazoles
Breast Neoplasms
Cell Line, Tumor
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Drug Resistance, Neoplasm
Female
Humans
Mice
Piperazines
Protein Kinase Inhibitors
Pyridines
Reactive Oxygen Species
Receptors, Estrogen
Xenograft Model Antitumor Assays