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posted on 2024-02-08, 08:20 authored by Belinda Kingston, Alex Pearson, Maria Teresa Herrera-Abreu, Li-Xuan Sim, Rosalind J. Cutts, Heena Shah, Laura Moretti, Lucy S. Kilburn, Hannah Johnson, Iain R. Macpherson, Alistair Ring, Judith M. Bliss, Yingwei Hou, Weiyi Toy, John A. Katzenellenbogen, Sarat Chandarlapaty, Nicholas C. Turner Transcriptomic analysis of ESR1-mutant models. A, Gene set enrichment analysis (GSEA) for D538G + F404L models compared with D538G D6C cells maintained in 1 nmol/L estradiol. Pathways are highlighted red; false discovery rate-adjusted q value <0.05. B, GSEA for D538G + F404L models compared with D538G D6C cells treated with 1 μmol/L fulvestrant for 24 hours. Pathways are highlighted red; false discovery rate-adjusted q value <0.05. C, GSEA for ESR1-mutant models. Normalized enrichment score (NES) is shown for the indicated pathways. *, False discovery rate-adjusted q value <0.05. D, Heat map of “Estrogen response late” genes (log2 expression) for ESR1-mutant models maintained in 1 nmol/L estradiol. E, Heat map of “Estrogen response late” genes (log2 expression) for ESR1-mutant models treated with 1 μmol/L fulvestrant in the presence of 1 nmol/L estradiol.
Funding
Cancer Research UK (CRUK)
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research (BRC)
Breast Cancer Now (BCN)
History
ARTICLE ABSTRACT
Fulvestrant is used to treat patients with hormone receptor–positive advanced breast cancer, but acquired resistance is poorly understood. PlasmaMATCH Cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Baseline ESR1 mutations Y537S are associated with poor outcomes and Y537C with good outcomes. Sequencing of baseline and EOT ctDNA samples (n = 69) revealed 3/69 (4%) patients acquired novel ESR1 F404 mutations (F404L, F404I, and F404V), in cis with activating mutations. In silico modeling revealed that ESR1 F404 contributes to fulvestrant binding to estrogen receptor–alpha (ERα) through a pi-stacking bond, with mutations disrupting this bond. In vitro analysis demonstrated that single F404L, E380Q, and D538G models were less sensitive to fulvestrant, whereas compound mutations D538G + F404L and E380Q + F404L were resistant. Several oral ERα degraders were active against compound mutant models. We have identified a resistance mechanism specific to fulvestrant that can be targeted by treatments in clinical development.
Novel F404 ESR1 mutations may be acquired to cause overt resistance to fulvestrant when combined with preexisting activating ESR1 mutations. Novel combinations of mutations in the ER ligand binding domain may cause drug-specific resistance, emphasizing the potential of similar drug-specific mutations to impact the efficacy of oral ER degraders in development.This article is featured in Selected Articles from This Issue, p. 201
