ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
BET Bromodomain Inhibition Reverses CDK4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer via Induction of miR-34a-5p.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Next-generation CDK inhibitors in HR+/HER2- breast cancer.The Journal of clinical investigation · 2026Review
- MicroRNAs and Alarmins in Cardio-Oncology: Biomarkers and Therapeutic Implications in Skin and Breast Cancer.International journal of molecular sciences · 2026Review
- Integrative Transcriptional and Chromatin Analyses Reveal Enhancer-Mediated Regulatory Programs Driving Breast Cancer Metastasis.Molecular cancer research : MCR · 2026Article
- Hippo pathway at the crossroads of stemness and therapeutic resistance in breast cancer.Molecular oncology · 2026Review
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
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Authors and funding
10 authors.
Funding
Abstract
purposeCDK6 overexpression is one critical determinant of acquired CDK4/6 inhibitor resistance. Because BRD4 is recruited to the CDK6 promoter, we investigated the potential of bromodomain and extraterminal domain (BET) inhibition to reverse CDK4/6 inhibitor resistance. EXPERIMENTAL
designCell viability and survival assays and cell line xenografts were used to evaluate BET inhibition in palbociclib-resistant breast cancer cells. Vehicle- and BET inhibitor-treated cells were subjected to RNA sequencing. CDK6 promoter activity was assessed with luciferase assays, and the miRPathDB version 2.0 database was used to identify potential miRNA mediating the effects of BET inhibition. Experiments were conducted to determine whether continued palbociclib treatment is essential for BET inhibitor efficacy and to explore associated mechanisms.
resultsIn CDK4/6 inhibitor-resistant models overexpressing CDK6, a cell-cycle gene signature was differentially downregulated following BET inhibition. The BET inhibitors JQ1 and ZEN-3694 reduced the expression of CDK6 and cyclin D1, reinstated CDK4/6 inhibitor-induced cell-cycle arrest, and triggered apoptosis in vitro, as well as tumor regression in vivo. Mechanistically, BET inhibition downregulated CDK6 expression through the induction of miR-34a-5p, rather than by directly repressing the CDK6 promoter. Introduction of a miR-34a-5p inhibitor abrogated BET inhibitor-mediated molecular changes, whereas a miR-34a-5p mimic replicated the effects of BET inhibition. Lastly, resistant cells exhibited downregulation of BCL-2 in the presence of continued palbociclib, associated with reduced estrogen receptor alpha expression, facilitating sensitivity to BET inhibition.
conclusionsOur findings highlight BET inhibition or the application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers.
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