期刊
BMC CANCER
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12885-016-2452-5
关键词
Tamoxifen resistance; Breast cancer; High-throughput drug testing; Exome-sequencing; Drug resistance
类别
资金
- Academy of Finland [269862, 272437, 279163]
- European Union [258068]
- EU-FP7-Systems Microscopy NoE
- Academy of Finland Centre of Excellence, Integrative Life Science (ILS) doctoral program
- Sigrid Juselius Foundation
- Cancer Society of Finland
- Cancer Foundation Finland sr [160080, 140114, 140087] Funding Source: researchfish
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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