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基于 SERM/SERD 的巴多昔芬破坏 ESR1 螺旋 12，以克服乳腺癌细胞获得性激素耐药性。

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

机构信息

Ben May Department for Cancer Research, University of Chicago, Chicago, United States.

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States.

出版信息

Elife. 2018 Nov 29;7:e37161. doi: 10.7554/eLife.37161.

DOI:10.7554/eLife.37161
PMID:30489256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6335054/
Abstract

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the (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.

摘要

获得性内分泌治疗耐药仍是乳腺癌患者的重大临床负担。雌激素受体 alpha (ERα) 基因配体结合域 (LBD) 的体细胞突变是获得性耐药的一种公认机制。与他莫昔芬相比，疗效改善的抗雌激素药物可能克服 ER +乳腺癌的耐药表型。Bazedoxifene (BZA) 是一种有效的抗雌激素药物，已被临床批准用于激素替代疗法。我们发现 BZA 对 Y537S 和 D538G ERα 突变体的抑制作用比他莫昔芬更强，并与 CDK4/6 抑制剂 palbociclib 联合具有额外的抑制活性。此外，综合生物物理和结构生物学研究表明，BZA 具有选择性雌激素受体降解 (SERD) 特性，可克服 Y537S 和 D538G ERα 突变的稳定作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/5593a61666cd/elife-37161-fig8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/8a46d86411d4/elife-37161-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/432cc31f8b30/elife-37161-fig6-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/550e3c4712a2/elife-37161-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/5593a61666cd/elife-37161-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/66ab5618496e/elife-37161-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/c5e1594fb990/elife-37161-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/4541bd44a03d/elife-37161-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/f22433f0efad/elife-37161-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/9e63511ef199/elife-37161-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/936089f3a326/elife-37161-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/bd4f973cc3e0/elife-37161-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/b87e5d3ba208/elife-37161-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/8a46d86411d4/elife-37161-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/432cc31f8b30/elife-37161-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/39c0f90afad5/elife-37161-fig6-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/e05db2c71d56/elife-37161-fig6-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/550e3c4712a2/elife-37161-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5934/6335054/5593a61666cd/elife-37161-fig8.jpg

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