Understanding drugs in breast cancer through drug sensitivity screening

Abstract

With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1406-8) contains supplementary material, which is available to authorized users.

MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines

“…In the analysis we combined the data of 36 cell lines for which 34 drugs gave differential responses among the included cell lines [40] and the expression data of 411 miRNAs [17].…”

“…Drug screening data was previously published for an extended cell line panel and the detailed description of drug-drug relations as well as the entire drug response dataset is available there [40]. In brief: The breast cancer cell lines were cultured and plated in triplicate in 96-well collagen-coated plates, and then incubated for 96 hours with 12 serial dilutions of 37 drugs or vehicle per cell line.…”

“…The drugs were supplied by Janssen Pharmaceutica (Beerse, Belgium) except for Veliparib, which was supplied by Abbott Laboratories (North Chicago, IL, USA). After 96 hours the Sulforhodamine B Assay was used to quantify total protein as a measure of cell number [41] and IC 50 values were computed subsequently [40]. Three drugs did not exhibit differential responses among the cell lines and were excluded from the final dataset [40].…”

“…After 96 hours the Sulforhodamine B Assay was used to quantify total protein as a measure of cell number [41] and IC 50 values were computed subsequently [40]. Three drugs did not exhibit differential responses among the cell lines and were excluded from the final dataset [40]. Therefore, the present study included 34 drugs which were used for further analyses.…”

“…By inspecting the results of the drug screening it became evident that the IC 50 response curves for different drugs were very different across cell lines (see also Uhr et al . [40]). While for some drugs most cell lines had different IC 50 values, other drugs had a large number of cell lines with the same IC 50 value up to almost all cell lines having identical IC 50 values.…”