Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers.

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  • Additional Information
    • Affiliation:
      Department of Obstetrics and Gynecology, University of Texas Health, 78229, San Antonio, TX, USA
      Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, 75390, Dallas, TX, USA
      CDP Program, University of Texas Health Cancer Center, 78229, San Antonio, TX, USA
      Department of Chemistry and Biochemistry, University of Texas at Dallas, 75080, Richardson, TX, USA
      Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, 75390, Dallas, TX, USA
      Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, 75390, Dallas, TX, USA
      Department of Cell Systems and Anatomy, University of Texas Health, 78229, San Antonio, TX, USA
      Department of Biochemistry and Structural Biology, University of Texas Health, 78229, San Antonio, TX, USA
    • Subject Terms:
    • Subject Terms:
    • Abstract:
      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.
    • Journal Subset:
      Biomedical; Blind Peer Reviewed; Editorial Board Reviewed; Europe; Expert Peer Reviewed; Peer Reviewed; UK & Ireland
    • Instrumentation:
      Global Assessment of Functioning Scale (GAF)
    • ISSN:
      1465-5411
    • MEDLINE Info:
      PMID: NLM31878959 NLM UID: 100927353
    • Grant Information:
      P30 CA054174/CA/NCI NIH HHS/United States; R01 CA179120/CA/NCI NIH HHS/United States
    • Publication Date:
      In Process
    • Publication Date:
      20200520
    • DOI:
      http://dx.doi.org/10.1186/s13058-019-1227-8
    • Accession Number:
      140850631
  • Citations
    • ABNT:
      VISWANADHAPALLI, S. et al. Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers. Breast Cancer Research, [s. l.], v. 21, n. 1, p. 1–15, 2019. DOI 10.1186/s13058-019-1227-8. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=140850631. Acesso em: 7 ago. 2020.
    • AMA:
      Viswanadhapalli S, Ma S, Sareddy GR, et al. Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers. Breast Cancer Research. 2019;21(1):1-15. doi:10.1186/s13058-019-1227-8
    • APA:
      Viswanadhapalli, S., Ma, S., Sareddy, G. R., Lee, T.-K., Li, M., Gilbreath, C., Liu, X., Luo, Y., Pratap, U. P., Zhou, M., Blatt, E. B., Kassees, K., Arteaga, C., Alluri, P., Rao, M., Weintraub, S. T., Tekmal, R. R., Ahn, J.-M., Raj, G. V., & Vadlamudi, R. K. (2019). Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers. Breast Cancer Research, 21(1), 1–15. https://doi.org/10.1186/s13058-019-1227-8
    • Chicago/Turabian: Author-Date:
      Viswanadhapalli, Suryavathi, Shihong Ma, Gangadhara Reddy Sareddy, Tae-Kyung Lee, Mengxing Li, Collin Gilbreath, Xihui Liu, et al. 2019. “Estrogen Receptor Coregulator Binding Modulator (ERX-11) Enhances the Activity of CDK4/6 Inhibitors against Estrogen Receptor-Positive Breast Cancers.” Breast Cancer Research 21 (1): 1–15. doi:10.1186/s13058-019-1227-8.
    • Harvard:
      Viswanadhapalli, S. et al. (2019) ‘Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers’, Breast Cancer Research, 21(1), pp. 1–15. doi: 10.1186/s13058-019-1227-8.
    • Harvard: Australian:
      Viswanadhapalli, S, Ma, S, Sareddy, GR, Lee, T-K, Li, M, Gilbreath, C, Liu, X, Luo, Y, Pratap, UP, Zhou, M, Blatt, EB, Kassees, K, Arteaga, C, Alluri, P, Rao, M, Weintraub, ST, Tekmal, RR, Ahn, J-M, Raj, GV & Vadlamudi, RK 2019, ‘Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers’, Breast Cancer Research, vol. 21, no. 1, pp. 1–15, viewed 7 August 2020, .
    • MLA:
      Viswanadhapalli, Suryavathi, et al. “Estrogen Receptor Coregulator Binding Modulator (ERX-11) Enhances the Activity of CDK4/6 Inhibitors against Estrogen Receptor-Positive Breast Cancers.” Breast Cancer Research, vol. 21, no. 1, Dec. 2019, pp. 1–15. EBSCOhost, doi:10.1186/s13058-019-1227-8.
    • Chicago/Turabian: Humanities:
      Viswanadhapalli, Suryavathi, Shihong Ma, Gangadhara Reddy Sareddy, Tae-Kyung Lee, Mengxing Li, Collin Gilbreath, Xihui Liu, et al. “Estrogen Receptor Coregulator Binding Modulator (ERX-11) Enhances the Activity of CDK4/6 Inhibitors against Estrogen Receptor-Positive Breast Cancers.” Breast Cancer Research 21, no. 1 (December 26, 2019): 1–15. doi:10.1186/s13058-019-1227-8.
    • Vancouver/ICMJE:
      Viswanadhapalli S, Ma S, Sareddy GR, Lee T-K, Li M, Gilbreath C, et al. Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers. Breast Cancer Research [Internet]. 2019 Dec 26 [cited 2020 Aug 7];21(1):1–15. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=140850631