ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer.
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Authors
Kingston, B
Pearson, A
Herrera-Abreu, MT
Sim, L-X
Cutts, RJ
Shah, H
Moretti, L
Kilburn, LS
Johnson, H
Macpherson, IR
Ring, A
Bliss, JM
Hou, Y
Toy, W
Katzenellenbogen, JA
Chandarlapaty, S
Turner, NC
Pearson, A
Herrera-Abreu, MT
Sim, L-X
Cutts, RJ
Shah, H
Moretti, L
Kilburn, LS
Johnson, H
Macpherson, IR
Ring, A
Bliss, JM
Hou, Y
Toy, W
Katzenellenbogen, JA
Chandarlapaty, S
Turner, NC
Document Type
Journal Article
Date
2024-02-08
Date Accepted
2023-11-16
Abstract
UNLABELLED: 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. SIGNIFICANCE: 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.
Citation
Cancer Discovery, 2023,
Source Title
Cancer Discovery
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
2159-8290
2159-8290
Collections
Research Team
Molecular Oncology
Clin Trials & Stats Unit
Clin Trials & Stats Unit