Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility

  • Cell. 2019 Aug 8;178(4):949-963.e18. doi: 10.1016/j.cell.2019.06.026.
Jane Guan  1 ,  Wei Zhou  1 ,  Marc Hafner  2 ,  Robert A Blake  3 ,  Cecile Chalouni  4 ,  Irene P Chen  5 ,  Tom De Bruyn  6 ,  Jennifer M Giltnane  4 ,  Steven J Hartman  7 ,  Amy Heidersbach  8 ,  Rene Houtman  9 ,  Ellen Ingalla  1 ,  Lorn Kategaya  10 ,  Tracy Kleinheinz  3 ,  Jun Li  11 ,  Scott E Martin  12 ,  Zora Modrusan  8 ,  Michelle Nannini  1 ,  Jason Oeh  1 ,  Savita Ubhayakar  5 ,  Xiaojing Wang  11 ,  Ingrid E Wertz  12 ,  Amy Young  1 ,  Mamie Yu  12 ,  Deepak Sampath  13 ,  Jeffrey H Hager  10 ,  Lori S Friedman  1 ,  Anneleen Daemen  2 ,  Ciara Metcalfe  14
Affiliations
  • 1. Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
  • 2. Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA.
  • 3. Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA 94080, USA.
  • 4. Department of Pathology, Genentech, South San Francisco, CA 94080, USA.
  • 5. Department of Medicine, UCSF, San Francisco, CA 94143, USA.
  • 6. Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA.
  • 7. Theravance Biopharma, South San Francisco, CA 94080, USA.
  • 8. Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
  • 9. Department of Research and Development, PamGene, 5211 HH's-Hertogenbosch, the Netherlands.
  • 10. Ideaya Biosciences, South San Francisco, CA 94080, USA.
  • 11. Department of Discovery Chemistry, Genentech, South San Francisco, CA 94080, USA.
  • 12. Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
  • 13. Department of Research, Ultragenyx, Novato, CA 94949, USA.
  • 14. Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 31353221 DOI: 10.1016/j.cell.2019.06.026
Abstract

Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast Cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.

Keywords
ER; SERD; breast cancer; chromatin; estrogen receptor; fulvestrant; immobilization; selective ER downregulator; transcription.
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