Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer

Show full item record



Permalink

http://hdl.handle.net/10138/165052

Citation

Kangaspeska , S , Hultsch , S , Jaiswal , A , Edgren , H , Mpindi , J-P , Eldfors , S , Bruck , O , Aittokallio , T & Kallioniemi , O 2016 , ' Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer ' , BMC Cancer , vol. 16 , 378 . https://doi.org/10.1186/s12885-016-2452-5

Title: Systematic drug screening reveals specific vulnerabilities and co-resistance patterns in endocrine-resistant breast cancer
Author: Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Bruck, Oscar; Aittokallio, Tero; Kallioniemi, Olli
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2016-07-04
Language: eng
Number of pages: 17
Belongs to series: BMC Cancer
ISSN: 1471-2407
URI: http://hdl.handle.net/10138/165052
Abstract: Background: The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Methods: Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. Results: We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome-and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. Conclusion: This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.
Subject: Tamoxifen resistance
Breast cancer
High-throughput drug testing
Exome-sequencing
Drug resistance
ESTROGEN-RECEPTOR-ALPHA
GROWTH-FACTOR RECEPTOR
COPY-NUMBER ALTERATION
ACTIVATED PROTEIN-KINASE
TAMOXIFEN RESISTANCE
ANTIESTROGEN RESISTANCE
FUNCTIONAL SCREEN
MCF-7 CELLS
IN-VITRO
ER-ALPHA
3122 Cancers
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Systematic_drug_screening.pdf 1.185Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record