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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 7

OTX015 suppresses growth of T-47D cells expressing ESR1 Y537S mutation.

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OTX015 suppresses growth of T-47D cells expressing ESR1 Y537S mutation.
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(A) Schematic representations of competition-based growth analyses performed using mixtures of T-47D cells generated by spike-in of CRISPR-engineered D538G (upper panel, blue) or Y537S (lower panel, red) clones into the nonmutated parental T-47D cell line. Pretreatment mutant allele frequency (MAF) was quantified by duplex digital PCR (dPCR), and total counts of mutant cell clones are also indicated. These cell line mixtures were cultured for 5 weeks in the presence of either DMSO, 1 μM tamoxifen, or 1 μM OTX015. The endpoint allele frequencies for D538G (upper panels, blue) or Y537S (lower panels, red) and the total cell numbers of the mutant clones are indicated for the endpoint of the drug treatment study. (B–D) Analysis of MAF and total cell counts were used to generate growth curves or cumulative population doublings for ESR1-WT (black) (B), ESR1-D538G (blue) (C), and ESR1 Y537S (red) (D) clones during exposure to DMSO, 1 μM tamoxifen, or 1 μM (OTX015). 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 ≤ 0.0005. Representative results from 1 of 3 independent experiments are shown.

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