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



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

Publisher: BIOMED CENTRAL LTD

: London

: 2016

BMC Cancer

BMC CANCER

: BMC CANCER

: ARTN 378

: 16

: 17

: 1471-2407

DOI: https://doi.org/10.1186/s12885-016-2452-5


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.

Last updated on 2024-26-11 at 19:58