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 5

BET inhibition synergizes with abemaciclib in inhibiting the growth of MCF-7 Y537S cells and xenografts.

Options: View larger image (or click on image) Download as PowerPoint
BET inhibition synergizes with abemaciclib in inhibiting the growth of M...
(A, D, and G) Combination matrices were prepared in 384-well microtitier plates, and Y537S MCF-7 cell viability was tested for the following conditions: abemaciclib versus abemaciclib (sham) (A), abemaciclib versus OTX15 (D), and OTX015 versus OTX015 (sham) (G). Concentrations of each drug increase from left to right (0.004, 0.011, 0.033, 0.1, 0.3, 0.9, and 2.7 μM) and from bottom to top (0.004, 0.011, 0.033, 0.1, 0.3, 0.9, and 2.7 μM) with zero drug in the lower left corner of each matrix. (B, E, and H) The additive condition was calculated for each experiment using the Loewe model. (C, F, I, and J) Excess volume (observed – model) was calculated for each experiment (C, F, and I), and synergy scores were determined (J) as previously described (51). (K) MCF-7 Y537S cells were implanted s.c. into athymic, nude mice without exogenous β-estradiol supplementation. When tumors reached 300–400 mm3, mice were randomized (n = 10 tumors/arm) to receive vehicle, OTX015 (100 mg/kg daily by oral gavage, 6 days/week), abemaciclib (50 mg/kg by oral gavage, 6 days/ week) + fulvestrant (1 mg sub-cutaneous injection weekly), or OTX015 + abemaciclib as indicated. The results were plotted as average tumor volume measured for each group ± SEM. To correct for multiple comparisons, ANOVA with Dunnett’s test was used to compare various experimental arms with the vehicle arm. Nonparametric Wilcoxon rank-sum test with Bonferroni correction was used for comparing treatment groups. **P ≤0.005.

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

Sign up for email alerts