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 (ET) targeting ER are central to treating hormone receptor-positive breast cancer (BC), 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 BC pre-clinical models, including models harboring the Y537S ESR1 mutation, an activating mutation. Imlunestrant demonstrated antagonistic activity and effective degradation of both wild-type 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 gained 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.