TCB Publications - Abstract

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, and Geoffrey L Greene. The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells. eLife, 7:e37161, 2018. (PMC: PMC6335054)

FANN2018-ET Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ER$\alpha$)) 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 ER$\alpha$ 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 ER$\alpha$ mutations.

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