Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Targeting ESR1 mutation–induced transcriptional addiction in breast cancer with BET inhibition
Sm N. Udden, … , Cheng-Ming Chiang, Prasanna G. Alluri
Sm N. Udden, … , Cheng-Ming Chiang, Prasanna G. Alluri
Published July 26, 2022
Citation Information: JCI Insight. 2022;7(17):e151851. https://doi.org/10.1172/jci.insight.151851.
View: Text | PDF
Research Article Oncology

Targeting ESR1 mutation–induced transcriptional addiction in breast cancer with BET inhibition

  • Text
  • PDF
Abstract

Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1,200 Federal Drug Administration–approved (FDA-approved) drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib + fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with WT cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant–induced endocrine therapy resistance in breast cancer.

Authors

Sm N. Udden, Qian Wang, Sunil Kumar, Venkat S. Malladi, Shwu-Yuan Wu, Shuguang Wei, Bruce A. Posner, Sophie Geboers, Noelle S. Williams, Yulun Liu, Jayesh K. Sharma, Ram S. Mani, Srinivas Malladi, Karla Parra, Mia Hofstad, Ganesh V. Raj, Jose M. Larios, Reshma Jagsi, Max S. Wicha, Ben Ho Park, Gaorav P. Gupta, Arul M. Chinnaiyan, Cheng-Ming Chiang, Prasanna G. Alluri

×

Figure 1

ESR1 mutations confer estrogen-independent growth in vivo.

Options: View larger image (or click on image) Download as PowerPoint

ESR1 mutations confer estrogen-independent growth in vivo.
(A and B) MC...
(A and B) MCF-7 cells harboring WT or mutant (Y537S or D538G) ESR1 were hormone deprived for 3 days and plated at a density of 10,000 cells per well in a 6-well plate in triplicate. Cells were allowed to grow for 6 days, and cell viability was quantified by crystal violet staining. (C) MCF-7 cells harboring WT or ESR1 Y537S or D538G mutations were hormone deprived for 3 days, and lysates were immunoblotted as indicated. (D and E) MCF-7 cells harboring WT, D538G, or Y537S mutations and stably transfected with a luciferase reporter were injected s.c. (5 million cells/injection) in the flanks of ovariectomized, NOD-SCID mice (n = 6 tumors) and allowed to grow without exogenous β-estradiol supplementation. Tumors were resected at the end of week 6 (D), and tumor volumes were quantified (E). Statistical significance was evaluated using ANOVA with Dunnett’s test to adjust for multiple comparisons. ***P ≤ 0.0005. (F and G) Heatmap showing differentially regulated genes in MCF-7 cells harboring D538G (F) or Y537S mutation (G) relative to cells harboring WT ESR1 (FC > 2 and FDR < 0.05) in hormone-depleted conditions. Also shown are Venn diagrams depicting overlap between upregulated/downregulated genes in β-estradiol–stimulated WT cells and hormone-depleted mutant cells as indicated.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts