ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1-mutant breast cancer Journal Article

   

Authors:	Kingston, B.; Pearson, A.; Herrera-Abreu, M. T.; Sim, L. X.; Cutts, R. J.; Shah, H.; Moretti, L.; Kilburn, L. S.; Johnson, H.; Macpherson, I. R.; Ring, A.; Bliss, J. M.; Hou, Y.; Toy, W.; Katzenellenbogen, J. A.; Chandarlapaty, S.; Turner, N. C.
Article Title:	ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1-mutant breast cancer
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. 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. ©2023 The Authors; Published by the American Association for Cancer Research.
Keywords:	breast cancer; cohort analysis; in vitro study; drug therapy; computer model; fulvestrant; advanced breast cancer; human; female; article; circulating tumor dna; chloroplast dna
Journal Title:	Cancer Discovery
Volume:	14
Issue:	2
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2024-02-01
Start Page:	274
End Page:	289
Language:	English
DOI:	10.1158/2159-8290.Cd-22-1387
PUBMED:	37982575
PROVIDER:	scopus
PMCID:	PMC10850945
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85184663995&doi=10.1158%2f2159-8290.CD-22-1387&partnerID=40&md5=6dffa832dc222975c2595302049408d7
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/213820