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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 2

Pharmacological BET inhibition disrupts ESR1 mutant–driven transcriptional programs.

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Pharmacological BET inhibition disrupts ESR1 mutant–driven transcription...
(A) Schematic depiction of domain architecture of full length and a deletion construct of BRD4 lacking NPS. BD1, bromodomain I; BD2, bromodomain II; BID, basic residue-enriched interaction domain; ET, extraterminal domain; NPS, N-terminal cluster of phosphorylation sites; CTM, C-terminal motif. (B) FLAG-tagged BRD4 (full-length or deletion construct lacking NPS) and HA-tagged WT, Y537S, or D538G ERα were ectopically expressed in MCF-7 cells, and nuclear extracts were subjected to immunoprecipitation using α-FLAG antibody and analyzed for the presence of ERα. (C) Nuclear extracts from MCF-7 Y537S cells were subjected to immunoprecipitation with BRD4 antibody and analyzed for the presence of native ERα following treatment with vehicle or OTX015 (1 μM). (D and E) GSEA of genes differentially expressed in MCF-7 Y537S (D) and D538G cells (E) relative to the WT cells showing activation of ERα signaling. (F and G) GSEA of genes differentially expressed in MCF-7 Y537S (F) and D538G cells (G) following treatment with OTX015 showing suppression of ERα signaling.

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ISSN 2379-3708

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