Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells

被引:0
作者
Young, K. S. [1 ]
Hancock, G. R. [1 ]
Fink, E. C. [1 ]
Zigrossi, A. [1 ]
Flowers, B. [1 ]
Cooper, D. A. [2 ]
Nguyen, V. T. [2 ]
Martinez, M. C. [1 ]
Mon, K. S. [1 ]
Bosland, M. [3 ]
Zak, D. R. [1 ]
Runde, A. P. [1 ]
Sharifi, M. N. [4 ]
Kastrati, I. [1 ]
Minh, D. D. L. [2 ]
Kregel, S. [1 ]
Fanning, Sean W. [1 ]
机构
[1] Loyola Univ Chicago, Stritch Sch Med, Dept Canc Biol, Maywood, IL 50153 USA
[2] IIT, Dept Chem, Chicago, IL 60616 USA
[3] Univ Illinois, Dept Pathol, Chicago, IL 60607 USA
[4] Univ Wisconsin, Dept Med, Madison, WI 53705 USA
基金
美国国家卫生研究院;
关键词
ESTROGEN-RECEPTOR MODULATORS; AROMATASE INHIBITOR; ENDOCRINE THERAPY; GENE-EXPRESSION; COACTIVATOR; MUTATIONS; ALPHA; GROWTH; EFFICACY; DEGRADER;
D O I
10.1186/s13058-024-01945-z
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ER alpha) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ER alpha ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ER alpha breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ER alpha. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER + breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER + breast cancers.
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页数:17
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共 72 条
[1]   AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer [J].
Anzick, SL ;
Kononen, J ;
Walker, RL ;
Azorsa, DO ;
Tanner, MM ;
Guan, XY ;
Sauter, G ;
Kallioniemi, OP ;
Trent, JM ;
Meltzer, PS .
SCIENCE, 1997, 277 (5328) :965-968
[2]   Lipid tethering of breast tumor cells reduces cell aggregation during mammosphere formation [J].
Bhandary, Lekhana ;
Bailey, Patrick C. ;
Chang, Katarina T. ;
Underwood, Karen F. ;
Lee, Cornell J. ;
Whipple, Rebecca A. ;
Jewell, Christopher M. ;
Ory, Eleanor ;
Thompson, Keyata N. ;
Ju, Julia A. ;
Mathias, Trevor M. ;
Pratt, Stephen J. P. ;
Vitolo, Michele, I ;
Martin, Stuart S. .
SCIENTIFIC REPORTS, 2021, 11 (01)
[3]   Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial [J].
Bidard, Francois-Clement ;
Kaklamani, Virginia G. ;
Neven, Patrick ;
Streich, Guillermo ;
Montero, Alberto J. ;
Forget, Frederic ;
Mouret-Reynier, Marie-Ange ;
Sohn, Joo Hyuk ;
Taylor, Donatienne ;
Harnden, Kathleen K. ;
Khong, Hung ;
Kocsis, Judit ;
Dalenc, Florence ;
Dillon, Patrick M. ;
Babu, Sunil ;
Waters, Simon ;
Deleu, Ines ;
Saenz, Jose A. Garcia ;
Bria, Emilio ;
Cazzaniga, Marina ;
Lu, Janice ;
Aftimos, Philippe ;
Cortes, Javier ;
Liu, Shubin ;
Tonini, Giulia ;
Laurent, Dirk ;
Habboubi, Nassir ;
Conlan, Maureen G. ;
Bardia, Aditya .
JOURNAL OF CLINICAL ONCOLOGY, 2022, 40 (28) :3246-+
[4]   EFFECT OF AN AROMATASE INHIBITOR, 4-HYDROXY-4-ANDROSTENE-3,17-DIONE, ON ESTROGEN-DEPENDENT PROCESSES IN REPRODUCTION AND BREAST-CANCER [J].
BRODIE, AMH ;
SCHWARZEL, WC ;
SHAIKH, AA ;
BRODIE, HJ .
ENDOCRINOLOGY, 1977, 100 (06) :1684-1695
[5]   Molecular basis of agonism and antagonism in the oestrogen receptor [J].
Brzozowski, AM ;
Pike, ACW ;
Dauter, Z ;
Hubbard, RE ;
Bonn, T ;
Engstrom, O ;
Ohman, L ;
Greene, GL ;
Gustafsson, JA ;
Carlquist, M .
NATURE, 1997, 389 (6652) :753-758
[6]   Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer A Secondary Analysis of the BOLERO-2 Clinical Trial [J].
Chandarlapaty, Sarat ;
Chen, David ;
He, Wei ;
Sung, Patricia ;
Samoila, Aliaksandra ;
You, Daoqi ;
Bhatt, Trusha ;
Patel, Parul ;
Voi, Maurizio ;
Gnant, Michael ;
Hortobagyi, Gabriel ;
Baselga, Jose ;
Moynahan, Mary Ellen .
JAMA ONCOLOGY, 2016, 2 (10) :1310-1315
[7]  
Chang CY, 1999, MOL CELL BIOL, V19, P8226
[8]   Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ERD/HER2L breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2 [J].
Damodaran, S. ;
O'Sullivan, C. C. ;
Elkhanany, A. ;
Anderson, I. C. ;
Barve, M. ;
Blau, S. ;
Cherian, M. A. ;
Peguero, J. A. ;
Goetz, M. P. ;
Plourde, P., V ;
Portman, D. J. ;
Moore, H. C. F. .
ANNALS OF ONCOLOGY, 2023, 34 (12) :1131-1140
[9]   PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations [J].
Dolinsky, Todd J. ;
Czodrowski, Paul ;
Li, Hui ;
Nielsen, Jens E. ;
Jensen, Jan H. ;
Klebe, Gerhard ;
Baker, Nathan A. .
NUCLEIC ACIDS RESEARCH, 2007, 35 :W522-W525
[10]   In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells [J].
Dontu, G ;
Abdallah, WM ;
Foley, JM ;
Jackson, KW ;
Clarke, MF ;
Kawamura, MJ ;
Wicha, MS .
GENES & DEVELOPMENT, 2003, 17 (10) :1253-1270