Imlunestrant: A next-generation oral SERD overcomes ESR1 mutant resistance in estrogen receptor-positive breast cancer

Estrogen receptor alpha (ER) is a critical driver of tumorigenesis and tumor progression in most breast cancers. Endocrine therapies targeting the ER are the cornerstone treatments in hormone receptor-positive breast cancer. Resistance to these therapies poses a significant clinical challenge and is due to diverse mechanisms. Some of these mechanisms, particularly through estrogen independent activity and the ESR1 mutations, remain dependent on the estrogen axis providing a rationale for the development of next-generation endocrine therapies. This study investigates the preclinical efficacy of imlunestrant, a next-generation oral selective estrogen receptor degrader, in ER-positive breast cancer pre-clinical models, including models harboring the Y537S ESR1 mutation, a prevalent and potent ER activating mutation. Imlunetsrant demonstrated pure antagonistic activity and effective degradation of both wild-type and mutant ER, significantly suppressing cell growth. In vivo, imlunestrant outperformed fulvestrant leading to tumor regression in a patient derived xenograft harboring the Y537S ESR1 mutation. Cyclic multiplexed 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 gained after imlunestrant treatment, which provides a rational for future studies of combination treatments with imlunestrant. In summary, these results highlight the on target and selective potent activity of imlunestrant, which can circumvent resistance engendered by the Y537S ESR1 mutation and support the clinical development of imlunestrant. Overall design: Cell lines (MCF7 or T47D) with doxycycline-induclible expression of ER-Y537S were hormone-deprived and treated with or without DMSO, E2, Fulvestrant, or Imlunestrant for 6 or 12 hours. Following treatment cells were processed for mRNAseq.