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

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

  • Breast Cancer Res. 2019 Dec 26;21(1):150. doi: 10.1186/s13058-019-1227-8.
Suryavathi Viswanadhapalli 1,  Shihong Ma 2,  Gangadhara Reddy Sareddy 1 3,  Tae-Kyung Lee 4,  Mengxing Li 1,  Collin Gilbreath 2,  Xihui Liu 2,  Yiliao Luo 1,  Uday P Pratap 1,  Mei Zhou 1,  Eliot B Blatt 2,  Kara Kassees 4,  Carlos Arteaga 5,  Prasanna Alluri 6,  Manjeet Rao 7,  Susan T Weintraub 8,  Rajeshwar Rao Tekmal 1,  Jung-Mo Ahn 9,  Ganesh V Raj 10 11,  Ratna K Vadlamudi 12 13
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, TX, 78229, USA.
  • 2 Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
  • 3 CDP Program, University of Texas Health Cancer Center, San Antonio, TX, 78229, USA.
  • 4 Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, 75080, USA.
  • 5 Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
  • 6 Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
  • 7 Department of Cell Systems and Anatomy, University of Texas Health, San Antonio, TX, 78229, USA.
  • 8 Department of Biochemistry and Structural Biology, University of Texas Health, San Antonio, TX, 78229, USA.
  • 9 Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, 75080, USA. jungmo.ahn@utdallas.edu.
  • 10 Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA. ganesh.raj@utsouthwestern.edu.
  • 11 Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA. ganesh.raj@utsouthwestern.edu.
  • 12 Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
  • 13 CDP Program, University of Texas Health Cancer Center, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
PMID: 31878959 DOI: 10.1186/s13058-019-1227-8
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.

Keywords

Breast cancer; CDK4/6 inhibitor; ER coregulator modulator; ER coregulators; Estrogen receptor (ER); Palbociclib; Therapy-resistant breast cancer.

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