eLife (Nov 2018)
The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
- Sean W Fanning,
- Rinath Jeselsohn,
- Venkatasubramanian Dharmarajan,
- Christopher G Mayne,
- Mostafa Karimi,
- Gilles Buchwalter,
- René Houtman,
- Weiyi Toy,
- Colin E Fowler,
- Ross Han,
- Muriel Lainé,
- Kathryn E Carlson,
- Teresa A Martin,
- Jason Nowak,
- Jerome C Nwachukwu,
- David J Hosfield,
- Sarat Chandarlapaty,
- Emad Tajkhorshid,
- Kendall W Nettles,
- Patrick R Griffin,
- Yang Shen,
- John A Katzenellenbogen,
- Myles Brown,
- Geoffrey L Greene
Affiliations
- Sean W Fanning
- ORCiD
- Ben May Department for Cancer Research, University of Chicago, Chicago, United States
- Rinath Jeselsohn
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
- Venkatasubramanian Dharmarajan
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
- Christopher G Mayne
- ORCiD
- Department of Biochemistry, College of Medicine, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States
- Mostafa Karimi
- Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, Texas, United States
- Gilles Buchwalter
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States
- René Houtman
- PamGene International BV, ‘s-Hertogenbosch, The Netherlands
- Weiyi Toy
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Colin E Fowler
- ORCiD
- Ben May Department for Cancer Research, University of Chicago, Chicago, United States
- Ross Han
- Ben May Department for Cancer Research, University of Chicago, Chicago, United States
- Muriel Lainé
- Ben May Department for Cancer Research, University of Chicago, Chicago, United States
- Kathryn E Carlson
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
- Teresa A Martin
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
- Jason Nowak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
- Jerome C Nwachukwu
- ORCiD
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
- David J Hosfield
- Ben May Department for Cancer Research, University of Chicago, Chicago, United States
- Sarat Chandarlapaty
- ORCiD
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
- Emad Tajkhorshid
- ORCiD
- Department of Biochemistry, College of Medicine, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States
- Kendall W Nettles
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
- Patrick R Griffin
- ORCiD
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
- Yang Shen
- ORCiD
- Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, Texas, United States
- John A Katzenellenbogen
- ORCiD
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States
- Myles Brown
- ORCiD
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
- Geoffrey L Greene
- ORCiD
- Ben May Department for Cancer Research, University of Chicago, Chicago, United States
- DOI
- https://doi.org/10.7554/eLife.37161
- Journal volume & issue
-
Vol. 7
Abstract
Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.
Keywords
- breast cancer
- acquired drug resistance
- hormone therapy
- ESR1 Somatic Mutation
- estrogen receptor
- selective estrogen receptor Degrader
