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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.
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Research Article Oncology

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

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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

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Figure 3

OTX015 is one of the top inhibitors of ESR1 mutant cells relative to drugs in the Prestwick chemical library.

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OTX015 is one of the top inhibitors of ESR1 mutant cells relative to dru...
(A) A plot of relative activity of individual compounds in the Prestwick chemical library relative to OTX015 performed in MCF-7 Y537S cells. The screen was carried out at a drug concentration of 3 μM in a 384-well format. Cytotoxicity was assayed by luminescence using Cell Titer Glo. (B) A plot of log IC50 values of the top hits identified in the primary screen. Dose-response relationships for the top hits from the primary screen were established against the WT and the 2 mutant cells in a multi-dose format with 3 replicates per compound per dose per cell line. (C) Dose-response relationship curves for OTX015 against MCF-7 cells harboring ESR1 WT, Y537S, or D538G mutations. (D) MCF-7 or T-47D cells harboring WT or mutant (Y537S or D538G) ESR1 were plated at a density of 10,000 cells per well in a 6-well plate in triplicate. Cells were treated with the indicated drug at 1 μM concentration and allowed to grow for 6 days. Cell viability was quantified by crystal violet staining, and data were plotted as fraction survival relative to vehicle treatment. Statistical significance was evaluated using ANOVA with Dunnett’s test to adjust for multiple comparisons. ***P ≤ 0.0005; **P ≤ 0.005; *P ≤ 0.05 by ANOVA with Dunnett’s test and #P ≤ 0.05 by unpaired t test.

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