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

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Estrogen receptor 1 (ESR1) mutations drive resistance to endocrine therapy in metastatic breast cancer. Targeting DNA damage responses with PARP inhibitors shows promise for treating this resistant cancer subset.

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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.