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

doi:10.7554/eLife.37161

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. GriffinYang Shen, John A. Katzenellenbogen, Myles Brown, Geoffrey L. Greene

Research output: Contribution to journal › Article › peer-review

Abstract

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa)) 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 ERa 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.

Original language	English (US)
Article number	e37161
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.37161
State	Published - Nov 1 2018

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.37161

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Fanning, S. W., Jeselsohn, R., Dharmarajan, V., Mayne, C. G., Karimi, M., Buchwalter, G., Houtman, R., Toy, W., Fowler, C. E., Han, R., Lainé, M., Carlson, K. E., Martin, T. A., Nowak, J., Nwachukwu, J. C., Hosfield, D. J., Chandarlapaty, S., Tajkhorshid, E., Nettles, K. W., ... Greene, G. L. (2018). The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells. eLife, 7, Article e37161. https://doi.org/10.7554/eLife.37161

Fanning, SW, Jeselsohn, R, Dharmarajan, V, Mayne, CG, Karimi, M, Buchwalter, G, Houtman, R, Toy, W, Fowler, CE, Han, R, Lainé, M, Carlson, KE, Martin, TA, Nowak, J, Nwachukwu, JC, Hosfield, DJ, Chandarlapaty, S, Tajkhorshid, E, Nettles, KW, Griffin, PR, Shen, Y, Katzenellenbogen, JA, Brown, M & Greene, GL 2018, 'The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells', eLife, vol. 7, e37161. https://doi.org/10.7554/eLife.37161

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title = "The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells",

abstract = "Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa)) 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 ERa 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{\textquoteright}s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.",

author = "Fanning, {Sean W.} and Rinath Jeselsohn and Venkatasubramanian Dharmarajan and Mayne, {Christopher G.} and Mostafa Karimi and Gilles Buchwalter and Ren{\'e} Houtman and Weiyi Toy and Fowler, {Colin E.} and Ross Han and Muriel Lain{\'e} and Carlson, {Kathryn E.} and Martin, {Teresa A.} and Jason Nowak and Nwachukwu, {Jerome C.} and Hosfield, {David J.} and Sarat Chandarlapaty and Emad Tajkhorshid and Nettles, {Kendall W.} and Griffin, {Patrick R.} and Yang Shen and Katzenellenbogen, {John A.} and Myles Brown and Greene, {Geoffrey L.}",

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AU - Fanning, Sean W.

AU - Jeselsohn, Rinath

AU - Dharmarajan, Venkatasubramanian

AU - Mayne, Christopher G.

AU - Karimi, Mostafa

AU - Buchwalter, Gilles

AU - Houtman, René

AU - Toy, Weiyi

AU - Fowler, Colin E.

AU - Han, Ross

AU - Lainé, Muriel

AU - Carlson, Kathryn E.

AU - Martin, Teresa A.

AU - Nowak, Jason

AU - Nwachukwu, Jerome C.

AU - Hosfield, David J.

AU - Chandarlapaty, Sarat

AU - Tajkhorshid, Emad

AU - Nettles, Kendall W.

AU - Griffin, Patrick R.

AU - Shen, Yang

AU - Katzenellenbogen, John A.

AU - Brown, Myles

AU - Greene, Geoffrey L.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa)) 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 ERa 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.

AB - Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERa)) 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 ERa 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.

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The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

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