Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant...

Area of Science:

• Oncology
• Molecular Biology
• Metabolism

Background:

• Endocrine therapies are standard for ER-positive breast cancer but often fail, leading to recurrence.
• A persistent subpopulation of endocrine-tolerant cells drives residual disease and drug resistance.
• Understanding persister cell biology is crucial for improving treatment outcomes.

Purpose of the Study:

• To investigate the mechanisms of endocrine-tolerant breast cancer cell persistence.
• To identify therapeutic vulnerabilities in residual disease after endocrine therapy.
• To explore the role of metabolism and CDK4/6 signaling in persister cells.

Main Methods:

• Analysis of persister cells proliferating despite endocrine therapy.
• Investigated E2F transcription factor signaling and its relation to CDK4/6 inhibitors (CDK4/6i).
• Assessed metabolic alterations, including mitochondrial function and ROS production, in response to CDK4/6i.

Main Results:

• Endocrine-tolerant persisters showed activated metabolism and E2F signaling.
• CDK4/6i treatment slowed persister cell cycling but induced mitochondrial upregulation and increased ROS.
• Inhibition of mitochondrial complex I enhanced ROS and growth inhibition in sensitive and resistant cells.

Conclusions:

• Mitochondrial respiration is a key metabolic pathway in CDK4/6-tolerant persister cells.
• Targeting mitochondrial respiration, specifically complex I, offers a potential strategy to eradicate residual breast cancer.
• This approach may overcome endocrine resistance and improve outcomes for patients with advanced breast cancer.