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; Rene Houtman; Weiyi Toy; Colin E. Fowler; Muriel Lainé; Kathryn E Carlson; Teresa A. Martin; Jason Nowak; Jerome Nwachukwu; David J. Hosfield; Sarat Chandarlapaty; Emad Tajkhorshid; Kendall W. Nettles; Patrick R. Griffin; Yang Shen; John A. Katzenellenbogen; Myles Brown; Geoffrey L. Greene

doi:10.1101/306472

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 find 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 that BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

Significance Bazedoxifene (BZA) is a potent orally available antiestrogen that is clinically approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-hydroxytamoxifen.

Footnotes

Precis: Bazedoxifene’s SERD activities enable it to resist the impact of activating ESR1 mutations.
Conflicts of Interest: Giles Buchwalter is an employee and shareholder at Celgene. Rene Houtman is an employee at PamGene International.
Financial Support:
SWF: Susan G. Komen Foundation PDF14301382
SWF, BDG, CEF, ML, GLG, WT, SC: Department of Defense Breakthrough Award W81XWH-14-1-0360
JAK: NIH DK015556, Breast Cancer Research Foundation BCRF-17-083
SC: NCI Cancer Center Support Grant (CCSG, P30 CA08748) and NIH R01CA204999
YS: NIH R35GM124952 and NSF CCF-1546278

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