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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 4

Pharmacological BET inhibition blocks growth of tumor xenografts harboring ESR1 Y537S mutation.

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Pharmacological BET inhibition blocks growth of tumor xenografts harbori...
(A) MCF-7 Y537S cells were implanted s.c. into ovariectomized athymic, nude mice without exogenous β-estradiol supplementation. When tumors reached 150–200 mm3, mice were randomized (n = 8 tumors/arm) and received vehicle, OTX015 (100 mg daily by oral gavage, 6 days/week), fulvestrant (1 mg s.c. injection weekly), or OTX015 + fulvestrant as indicated. (B) WHIM20 cells harboring Y537S mutation were implanted s.c. into ovariectomized, NOD-SCID mice without exogenous β-estradiol supplementation. When tumors reached 150–200 mm3, mice were randomized (n = 6 tumors/arm) and received vehicle or OTX015 (100 mg daily by oral gavage, 6 days/week). The results were plotted as average tumor volume measured for each group ± SEM. (C) Reverse transcription-PCR for GREB1 in WHIM20 xenografts (n = 6) from vehicle and OTX015-treated mice. (D) Schematic representation of patient-derived xenograft explant assay. (E and F) WHIM20 explants (n = 3) were treated with vehicle, OTX015, JQ1, or I-BET762 at a 10 μM concentration for 48 hours, and effect on proliferation was measured by Ki-67 IHC staining. The quantification of the images was performed by the image analysis software ImageJ (NIH), and the results are shown as the ratio between the Ki-67+ area and the total area of the image. P values were determined using an unpaired, 2-tailed t test for pairwise comparisons. 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 ≤ 0.05; **P ≤ 0.005; ***P ≤ 0.0005.

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