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Updated: Nov 19, 2025
Detection of Rare Mutations in CtDNA Using Next Generation Sequencing
Published on: August 24, 2017
The ESR1 Mutations: From Bedside to Bench to Bedside
Francisco Hermida-Prado1,2, Rinath Jeselsohn3,2,4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Abstract:
The ESR1 ligand-binding mutations were unveiled a number of years ago and are the most common genetic mechanism of acquired resistance to endocrine treatment, particularly, to aromatase inhibitors. The discovery of these mutations was enabled after advancements in sequencing technologies and when metastatic tissue samples were interrogated. The ESR1 ligand-binding domain mutations are activating mutations that lead to constitutive ligand-independent activity, which explains the emergence of these mutations under the selective pressure of aromatase inhibitors. Arnesen and colleagues have generated new models of the ESR1 mutations using CRISPR technology to generate single-cell-derived clones in which the ESR1 ligand-binding mutations were "knocked-in" and expressed under the endogenous promoter of estrogen receptor. The authors have extensively characterized these models and have shed new light on the functional consequences ESR1 mutations.See related article by Arnesen et al., p. 539.
Insights
New models reveal how estrogen receptor 1 (ESR1) mutations drive resistance to endocrine therapies like aromatase inhibitors. These activating ESR1 mutations lead to continuous receptor activity, even without estrogen, explaining treatment failure.
Area of Science:
- Endocrinology
- Genetics
- Cancer Biology
Background:
- Estrogen receptor 1 (ESR1) ligand-binding domain mutations are the primary cause of acquired resistance to endocrine treatments, especially aromatase inhibitors.
- These mutations confer constitutive, ligand-independent activity to the estrogen receptor, explaining their emergence under selective pressure.
Purpose of the Study:
- To generate and characterize novel models of ESR1 ligand-binding domain mutations.
- To elucidate the functional consequences of these activating ESR1 mutations.
Main Methods:
- Utilized CRISPR technology to generate single-cell-derived clones with knocked-in ESR1 ligand-binding mutations.
- Expressed mutated ESR1 under its endogenous promoter in the generated models.
Main Results:
- Successfully created and extensively characterized novel models of ESR1 mutations.
- These models provide new insights into the functional impact of ESR1 mutations.
Conclusions:
- The developed models are crucial for understanding the mechanisms of endocrine resistance driven by ESR1 mutations.
- Further research using these models will illuminate the functional consequences of ESR1 mutations in endocrine therapy resistance.
