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Understanding drugs in breast cancer through drug sensitivity screening.

Uhr K, Prager-van der Smissen WJ, Heine AA, Ozturk B, Smid M, Göhlmann HW, Jager A, Foekens JA, Martens JW - Springerplus (2015)

Bottom Line: 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.We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Postbus 2040, 's-Gravendijkwal 230, 3000 CA Rotterdam, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

Nutlin-3 and MI-219 have similar drug sensitivity profiles among the cell lines (relative IC50 values). The relative IC50 is inverted, with high numbers indicating sensitivity in this case and not resistance. Few cell lines are sensitive to these drugs, while the majority is resistant
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Fig3: Nutlin-3 and MI-219 have similar drug sensitivity profiles among the cell lines (relative IC50 values). The relative IC50 is inverted, with high numbers indicating sensitivity in this case and not resistance. Few cell lines are sensitive to these drugs, while the majority is resistant

Mentions: Strong correlation and expected co-clustering was observed between Gefitinib and Erlotinib (cluster 1; r = 0.88), between Quisinostat, Panobinostat, Vorinostat and Belinostat (cluster 2; r = 0.85–0.96), between Docetaxel and Paclitaxel (cluster 3; r = 0.73), between JNJ-707 and JNJ-493 (cluster 4; r = 0.62) and between MI-219 and Nutlin-3 (cluster 6; r = 0.98); all correlations are listed additionally in Table 1. To illustrate the close relationship between related drugs, the IC50 values of MI-219 and Nutlin-3, the two drugs with the highest correlation, were ranked and plotted for all cell lines (Fig. 3). Interestingly, Serdemetan, a drug which acts on cholesterol transport but also targets MDM2 (Jones et al. 2013)—a mechanism shared with Nutlin-3 and MI-219 (Shangary and Wang 2009)—showed no correlation with these two compounds.Table 1


Understanding drugs in breast cancer through drug sensitivity screening.

Uhr K, Prager-van der Smissen WJ, Heine AA, Ozturk B, Smid M, Göhlmann HW, Jager A, Foekens JA, Martens JW - Springerplus (2015)

Nutlin-3 and MI-219 have similar drug sensitivity profiles among the cell lines (relative IC50 values). The relative IC50 is inverted, with high numbers indicating sensitivity in this case and not resistance. Few cell lines are sensitive to these drugs, while the majority is resistant
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4628005&req=5

Fig3: Nutlin-3 and MI-219 have similar drug sensitivity profiles among the cell lines (relative IC50 values). The relative IC50 is inverted, with high numbers indicating sensitivity in this case and not resistance. Few cell lines are sensitive to these drugs, while the majority is resistant
Mentions: Strong correlation and expected co-clustering was observed between Gefitinib and Erlotinib (cluster 1; r = 0.88), between Quisinostat, Panobinostat, Vorinostat and Belinostat (cluster 2; r = 0.85–0.96), between Docetaxel and Paclitaxel (cluster 3; r = 0.73), between JNJ-707 and JNJ-493 (cluster 4; r = 0.62) and between MI-219 and Nutlin-3 (cluster 6; r = 0.98); all correlations are listed additionally in Table 1. To illustrate the close relationship between related drugs, the IC50 values of MI-219 and Nutlin-3, the two drugs with the highest correlation, were ranked and plotted for all cell lines (Fig. 3). Interestingly, Serdemetan, a drug which acts on cholesterol transport but also targets MDM2 (Jones et al. 2013)—a mechanism shared with Nutlin-3 and MI-219 (Shangary and Wang 2009)—showed no correlation with these two compounds.Table 1

Bottom Line: 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.We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Postbus 2040, 's-Gravendijkwal 230, 3000 CA Rotterdam, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus