Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers.
Background: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen...
| Publicado en: | Breast Cancer Research Vol. 21; no. 1; pp. 1 - 16 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
12/26/2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=140850631&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 140850631 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 12/26/2019 vid: 21 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 140850631 140850631 NLM31878959 140850631 10.1186/s13058-019-1227-8 NLM31878959 140850631 ppf: 1 ppct: 15 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers. aug: au: Viswanadhapalli, Suryavathi Ma, Shihong Sareddy, Gangadhara Reddy Lee, Tae-Kyung Li, Mengxing Gilbreath, Collin Liu, Xihui Luo, Yiliao Pratap, Uday P. Zhou, Mei Blatt, Eliot B. Kassees, Kara Arteaga, Carlos Alluri, Prasanna Rao, Manjeet Weintraub, Susan T. Tekmal, Rajeshwar Rao Ahn, Jung-Mo Raj, Ganesh V. Vadlamudi, Ratna K. affil: Department of Obstetrics and Gynecology, University of Texas Health, 78229, San Antonio, TX, USA sug: subj: Transferases Antagonists and Inhibitors Estrogen Receptor Modulators Pharmacodynamics Breast Neoplasms Metabolism Protein Kinase Inhibitors Pharmacodynamics Proteins Metabolism Mice Drug Synergism Drug Evaluation, Preclinical Immunohistochemistry Cell Physiology Drug Effects Models, Biological Breast Neoplasms Pathology Animal Studies Breast Neoplasms Drug Therapy Female Human Drug Resistance, Neoplasm Cell Line, Tumor Validation Studies Comparative Studies Evaluation Research Multicenter Studies Scales Female ab: Background: CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent.Methods: We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity.Results: ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies.Conclusions: Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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