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Imlunestrant a next-generation oral SERD overcomes ESR1 mutant resistance in estrogen receptor-positive breast cancer
Shira Sherman1, Zachary M Sandusky1,2, Douglas Russo1,3,4
1Department of Medical Oncology and.
Abstract:
Estrogen receptor α (ER) is a critical driver of tumorigenesis and tumor progression in most breast cancers. Endocrine therapies (ET) targeting ER are central to treating hormone receptor-positive breast cancer, but resistance poses a clinical challenge. Some resistance mechanisms, particularly those involving estrogen-independent activity such as the ESR1 mutations, rely on ER signaling, supporting the need for next-generation ET. We investigated the preclinical efficacy of imlunestrant, an oral selective ER degrader, in ER-positive breast cancer preclinical models, including models harboring the Y537S ESR1 mutation, an activating mutation. Imlunestrant demonstrated antagonistic activity and effective degradation of both WT and mutant ER, resulting in cell growth suppression. In vivo, imlunestrant outperformed fulvestrant, leading to tumor regression in a patient-derived xenograft harboring the Y537S ESR1 mutation. Cyclic mutiplexed immunofluorescence and transcriptomic analysis revealed enhanced cell cycle arrest and downregulation of estrogen-responsive genes with imlunestrant treatment. Additionally, a genome-wide CRISPR knock-out screen identified several vulnerabilities that were either persistent or acquired after imlunestrant treatment, providing a rationale for future studies of combination treatments with imlunestrant. Collectively, these results highlight the on-target and selective activity of imlunestrant, which can circumvent resistance engendered by the Y537S ESR1 mutation.
Insights
Imlunestrant, a novel oral selective estrogen receptor degrader, effectively targets both wild-type and mutant ER in breast cancer models. This drug shows promise in overcoming endocrine therapy resistance, particularly ESR1 mutations.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Estrogen receptor alpha (ER) drives tumorigenesis in most breast cancers.
- Endocrine therapies (ET) targeting ER are standard for hormone receptor-positive breast cancer (BC).
- Resistance to ET, especially via ESR1 mutations, necessitates novel therapeutic strategies.
Purpose of the Study:
- To evaluate the preclinical efficacy of imlunestrant, an oral selective ER degrader.
- To assess imlunestrant's activity against ER-positive BC models, including those with the Y537S ESR1 mutation.
- To explore imlunestrant's potential to overcome ET resistance mechanisms.
Main Methods:
- Preclinical testing of imlunestrant in ER-positive BC cell lines and patient-derived xenografts.
- Inclusion of models with wild-type and Y537S mutated ESR1.
- Utilized cyclic multiplexed immunofluorescence, transcriptomic analysis, and genome-wide CRISPR screens.
Main Results:
- Imlunestrant demonstrated antagonistic activity and degraded both wild-type and mutant ER, suppressing cell growth.
- In vivo studies showed imlunestrant outperformed fulvestrant, inducing tumor regression in a Y537S ESR1 mutant xenograft model.
- Treatment led to cell cycle arrest, downregulated estrogen-responsive genes, and identified combination therapy vulnerabilities.
Conclusions:
- Imlunestrant exhibits potent, on-target activity against ER-positive breast cancer.
- It effectively circumvents resistance mediated by the Y537S ESR1 mutation.
- Imlunestrant represents a promising next-generation endocrine therapy for advanced breast cancer.
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