Defective DNA Damage Response Is a Targetable Therapeutic Vulnerability in ESR1-Mutant Breast Cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Estrogen receptor 1 (ESR1) mutations are a primary driver of endocrine therapy resistance and disease progression in ER-positive metastatic breast cancer.
• Approximately 50% of metastatic breast cancer patients harbor ESR1 mutations, necessitating the development of novel targeted therapies.

Purpose of the Study:

• To investigate the role of replication stress and DNA damage responses in ESR1-mutant breast cancer.
• To evaluate the therapeutic potential of targeting these pathways, particularly with PARP inhibitors, in ESR1-mutant metastatic breast cancer.

Main Methods:

• Analysis of ESR1 mutant models to identify dysregulated pathways.
• In vitro and in vivo studies combining checkpoint inhibitors with PARP inhibitors.
• Assessment of PARP trapping by olaparib and its interaction with ER-PARP1.
• Evaluation of abemaciclib-induced ESR1 mutations and subsequent pathway responses.
• Combination therapy studies with PARP inhibitors and endocrine therapy.

Main Results:

• ESR1 mutant models exhibit enrichment of dysregulated replication stress and DNA damage responses.
• Combined checkpoint and PARP inhibition synergistically suppressed tumor growth, induced cell cycle arrest, and reduced DNA replication.
• PARP inhibition blocked metastatic dissemination and reduced PARP1 and ER protein expression.
• Olaparib treatment increased co-localized DNA-bound PARP1 and ER protein in ESR1 mutant cells.
• Emergence of Y537S ESR1 mutation under abemaciclib treatment led to replication stress response dysregulation and synergistic responses to pathway inhibitors.
• PARP inhibition synergized with endocrine therapy, reducing tumor growth in ESR1 mutant models.

Conclusions:

• Replication stress and DNA damage responses are key dysregulated pathways in ESR1-mutant breast cancer.
• PARP inhibition demonstrates significant clinical potential as a targeted therapy for this metastatic breast cancer subset.
• Understanding ER-PARP1 co-regulation in ESR1 mutant cells offers new therapeutic insights.