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

Kangaspeska S; Bruck O; Aittokallio T; Mpindi JP; Hultsch S; Edgren H; Eldfors S; Jaiswal A; Kallioniemi O

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

Kangaspeska S
Bruck O
Aittokallio T
Mpindi JP
Hultsch S
Edgren H
Eldfors S
Jaiswal A
Kallioniemi O
Katso/Avaa
Publisher's version (1.189Mb)
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BIOMED CENTRAL LTD
doi:10.1186/s12885-016-2452-5
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042716065
Tiivistelmä
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.
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