The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Estrogen receptor (ER/ESR1) is crucial in most breast cancers, with ER signaling inhibitors forming the basis of treatment.
• Aromatase inhibitors are first-line endocrine therapies, but their efficacy in metastatic disease is limited by ESR1 mutations causing ligand-independent ER activation.
• ESR1 mutations may reduce the effectiveness of selective estrogen receptor downregulators and modulators (SERMs) in second-line therapies.

Purpose of the Study:

• To investigate the molecular mechanisms of ESR1-mutant pharmacology in models relevant to metastatic breast cancer.
• To determine how ESR1 mutations, coexpressed with wild-type ER (ERWT), affect cellular response to ER ligands.
• To evaluate the impact of ESR1 mutations on the efficacy of SERMs, specifically lasofoxifene.

Main Methods:

• Dissection of molecular mechanisms underlying ESR1-mutant pharmacology.
• Utilizing cell models relevant to metastatic breast cancer.
• Assessing the impact of relative coexpression of ERWT and ESR1 mutants on ligand response.

Main Results:

• The response of ESR1 mutations to ligands is primarily determined by the coexpression level of ERWT.
• Dysregulated ER pharmacology was observed only when ESR1 mutants were overexpressed relative to ligand-activated ERWT.
• The SERM lasofoxifene demonstrated consistent antagonist activity irrespective of ESR1 mutant status.

Conclusions:

• Allelism plays a key role in determining ER-mutant pharmacology.
• Lasofoxifene's preserved antagonist activity against ESR1 mutations supports its clinical evaluation for advanced ER-positive breast cancer with ESR1 mutations.
• These findings offer a potential therapeutic strategy for a subset of patients with treatment-resistant breast cancer.