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

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

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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 organization: Institute for Molecular Medicine Finland
Olli-Pekka Kallioniemi / Principal Investigator
Tero Aittokallio / Principal Investigator
Bioinformatics
Date: 2016-07-04
Language: eng
Number of pages: 17
Belongs to series: BMC Cancer
ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2452-5
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
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion


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