Imlunestrant, a next-generation oral SERD, overcomes ESR1 mutant resistance in estrogen receptor-positive breast cancer
Sherman S, Sandusky ZM, Russo D, Zak D, Nardone A, Friel D, et al.
JCI Insight. 2025;10(12). DOI 10.1172/jci.insight.188051. PMID 40327396. PMCID PMC12226049.
How to cite
AMA
Sherman S, Sandusky ZM, Russo D, Zak D, Nardone A, Friel D, et al. Imlunestrant, a next-generation oral SERD, overcomes ESR1 mutant resistance in estrogen receptor-positive breast cancer. JCI Insight. 2025;10(12). doi:10.1172/jci.insight.188051APA
Sherman, S., Sandusky, Z M., Russo, D., Zak, D., Nardone, A., Friel, D., et al. (2025). Imlunestrant, a next-generation oral SERD, overcomes ESR1 mutant resistance in estrogen receptor-positive breast cancer. JCI Insight, 10(12). https://doi.org/10.1172/jci.insight.188051BibTeX
@article{sherman2025imlunestrant,
title = {Imlunestrant, a next-generation oral SERD, overcomes ESR1 mutant resistance in estrogen receptor-positive breast cancer},
author = {Sherman, S and Sandusky, Z M and Russo, D and Zak, D and Nardone, A and Friel, D and others},
journal = {JCI Insight},
volume = {10},
number = {12},
year = {2025},
doi = {10.1172/jci.insight.188051},
pmid = {40327396}
}Many estrogen receptor-positive breast cancers eventually stop responding to endocrine therapy, and one common cause is a mutation in the ESR1 gene that locks the receptor in an active state even while the drug is present. Fulvestrant, a standard degrader, is given by injection and reaches these mutant tumors poorly.
This preclinical study characterized imlunestrant, an oral selective estrogen receptor degrader. It blocked and degraded both wild-type and Y537S-mutant receptor, suppressed the growth of resistant cell lines, and drove tumor regression in a patient-derived xenograft that no longer responded to fulvestrant. Single-cell imaging of the treated tumors showed imlunestrant pushed more cancer cells into cell-cycle arrest than fulvestrant did.
Key findings
- Oral imlunestrant drove tumor regression where fulvestrant could not. In a fulvestrant-resistant Y537S ESR1-mutant patient-derived xenograft, daily oral imlunestrant (15 mg/kg for 28 days) produced tumor regression, while weekly fulvestrant (5 mg) did not.
- Single-cell imaging separated arrested cells from proliferating ones. A Multivariate Proliferation Index built from three proliferation markers (Ki-67, MCM2, PCNA) and two arrest markers (p21, p27) showed imlunestrant produced deeper cell-cycle arrest than fulvestrant.
- A genome-wide CRISPR screen nominated a metabolic combination target. Screening roughly 117,587 guide RNAs against 18,000 genes in imlunestrant-treated cells flagged oxidative phosphorylation genes as newly essential, and an OXPHOS inhibitor (IACS-010759) suppressed growth of the ESR1-mutant cells.
CyteFinder in the methods
“The methods for CycIF and MPI calculation were previously described ( 19 ). Briefly, FFPE slides were baked at 60°C for 30 minutes, dewaxed using Bond Dewax solution at 72°C, and antigen retrieval was performed with Epitope Retrieval 1 solution at 100°C for 20 minutes using the BOND RX Automated IHC/ISH Stainer. Antibodies for each cycle were diluted in Odyssey Blocking Buffer and incubated overnight at 4°C in the dark. After antibody incubation, slides were stained with Hoechst 33342 for 10 minutes at room temperature. Slides were cover slipped using 20%–50% glycerol solution (Sigma-Aldrich, G5516) in PBS. Images were taken using DAPI, FITC, Cy3, and Cy5 channels either on the RareCyte CyteFinder (20x/0.75NA objective).”
— Sherman et al., JCI Insight (2025), Methods, “CyCIF MPI”
Why it matters for CyteFinder users
If you are weighing CyteFinder for tissue imaging, notice which question it answered here. Bulk immunohistochemistry can tell you that a tumor carries less Ki-67 after treatment, but it cannot tell you how each individual cell responded. The CyteFinder did the cyclic imaging that made the finer readout possible: FFPE tumor sections were stained, imaged across the DAPI, FITC, Cy3, and Cy5 channels with a 20x/0.75NA objective, and re-stained over successive cycles, so many markers were recorded on the same cells. From those multi-cycle images the authors computed a per-cell Multivariate Proliferation Index and could separate proliferating cells from arrested ones one cell at a time. Two things follow for your own work. Because every marker is registered on the same section, you read proliferation and arrest together rather than inferring them from serial slides. And because the readout is single-cell, you can show that a drug pushes a population into arrest, not merely that an average marker fell. That distinction is what carried the in-vivo comparison in this study.
