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dc.contributor.authorKingston, B
dc.contributor.authorPearson, A
dc.contributor.authorHerrera-Abreu, MT
dc.contributor.authorSim, L-X
dc.contributor.authorCutts, RJ
dc.contributor.authorShah, H
dc.contributor.authorMoretti, L
dc.contributor.authorKilburn, LS
dc.contributor.authorJohnson, H
dc.contributor.authorMacpherson, IR
dc.contributor.authorRing, A
dc.contributor.authorBliss, JM
dc.contributor.authorHou, Y
dc.contributor.authorToy, W
dc.contributor.authorKatzenellenbogen, JA
dc.contributor.authorChandarlapaty, S
dc.contributor.authorTurner, NC
dc.coverage.spatialUnited States
dc.date.accessioned2023-11-27T13:40:52Z
dc.date.available2023-11-27T13:40:52Z
dc.date.issued2024-02-08
dc.identifier730181
dc.identifier.citationCancer Discovery, 2023,
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/6073
dc.identifier.eissn2159-8290
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.CD-22-1387
dc.identifier.doi10.1158/2159-8290.CD-22-1387
dc.description.abstractUNLABELLED: 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.
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.relation.ispartofCancer Discovery
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer.
dc.typeJournal Article
dcterms.dateAccepted2023-11-16
dc.date.updated2023-11-23T15:05:19Z
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/2159-8290.CD-22-1387
rioxxterms.licenseref.startdate2023-11-20
rioxxterms.typeJournal Article/Review
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/37982575
pubs.organisational-groupICR
pubs.organisational-groupICR/Primary Group
pubs.organisational-groupICR/Primary Group/ICR Divisions
pubs.organisational-groupICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-groupICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-groupICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-groupICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-groupICR/Students
pubs.organisational-groupICR/Students/PhD and MPhil
pubs.organisational-groupICR/Students/PhD and MPhil/17/18 Starting Cohort
pubs.publication-statusPublished online
pubs.publisher-urlhttp://dx.doi.org/10.1158/2159-8290.cd-22-1387
icr.researchteamMolecular Oncology
icr.researchteamClin Trials & Stats Unit
dc.contributor.icrauthorKingston, Belinda
dc.contributor.icrauthorPearson, Alex
dc.contributor.icrauthorCutts, Rosalind
dc.contributor.icrauthorKilburn, Lucy
dc.contributor.icrauthorBliss, Judith
dc.contributor.icrauthorTurner, Nicholas
icr.provenanceDeposited by Dr Alex Pearson on 2023-11-23. Deposit type is initial. No. of files: 2. Files: F404 Supp figures_tables_methods reb_FINAL_pa.pdf; ESR1 F404 mutations_reb_FINAL_pa.pdf


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