The Experts below are selected from a list of 240 Experts worldwide ranked by ideXlab platform
Krister Wennerberg - One of the best experts on this subject based on the ideXlab platform.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular Cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Additional file 11: Figure S8. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Time dependent combination effect of Dactolisib and trametinib in DU4475 and MDA-MB-231 cell lines. Each matrix represents toxicity based delta score combination plot (red being synergistic and green being antagonistic). The toxicity readout was measured after 96 h from onset of screen disregarding different subsequent combination of drugs in different times to monitor (A) both drugs added together at 0 h, (B) Dactolisib added at the onset of experiment and then trametinib combined after 24 h, (C) Dactolisib added at the onset of experiment and then trametinib combined after 48 h. (PDF 145 kb
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Additional file 8: Figure S4. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:ATP-competitive mTOR inhibitors antagonize the effect of diverse classes of compounds in CAL-51. (A) Scatter plot of DSS scored for combinatory effect of different compounds along with Dactolisib (Y-axis) on CAL-51 cell line compared to their single compound effect (X-axis). The right-hand plot represents the DSS computed using viability assay and the left plot represents cell death assay. Data points with DSS difference more than 10 are highlighted with different colors representing different classes of agents as listed in the color legend. (PDF 118 kb
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Additional file 9: Figure S5. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Cell line specific synergistic drug combination effects. Blue 8 × 8 blue matrices show % viability inhibition whereas red matrices show % cell death as similar represented in Fig. 7 and likewise 7 × 7 matrix represents synergy score. (A) Combining Dactolisib and everolimus resulted in enhancing both viability inhibition and cytotoxicity in CAL-148 and DU4475 cell lines and only increased viability inhibition in MDA-MB-231 but did not show any additive effect in cytotoxicity. (B) The synergistic effect of combining trametinib with iniparib and ponatinib was only seen in DU4475 but not in CAL-148 cell line. (PDF 118 kb
Prson Gautam - One of the best experts on this subject based on the ideXlab platform.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular Cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Additional file 11: Figure S8. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Time dependent combination effect of Dactolisib and trametinib in DU4475 and MDA-MB-231 cell lines. Each matrix represents toxicity based delta score combination plot (red being synergistic and green being antagonistic). The toxicity readout was measured after 96 h from onset of screen disregarding different subsequent combination of drugs in different times to monitor (A) both drugs added together at 0 h, (B) Dactolisib added at the onset of experiment and then trametinib combined after 24 h, (C) Dactolisib added at the onset of experiment and then trametinib combined after 48 h. (PDF 145 kb
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Additional file 8: Figure S4. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:ATP-competitive mTOR inhibitors antagonize the effect of diverse classes of compounds in CAL-51. (A) Scatter plot of DSS scored for combinatory effect of different compounds along with Dactolisib (Y-axis) on CAL-51 cell line compared to their single compound effect (X-axis). The right-hand plot represents the DSS computed using viability assay and the left plot represents cell death assay. Data points with DSS difference more than 10 are highlighted with different colors representing different classes of agents as listed in the color legend. (PDF 118 kb
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Additional file 9: Figure S5. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Cell line specific synergistic drug combination effects. Blue 8 × 8 blue matrices show % viability inhibition whereas red matrices show % cell death as similar represented in Fig. 7 and likewise 7 × 7 matrix represents synergy score. (A) Combining Dactolisib and everolimus resulted in enhancing both viability inhibition and cytotoxicity in CAL-148 and DU4475 cell lines and only increased viability inhibition in MDA-MB-231 but did not show any additive effect in cytotoxicity. (B) The synergistic effect of combining trametinib with iniparib and ponatinib was only seen in DU4475 but not in CAL-148 cell line. (PDF 118 kb
Tero Aittokallio - One of the best experts on this subject based on the ideXlab platform.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular Cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Additional file 11: Figure S8. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Time dependent combination effect of Dactolisib and trametinib in DU4475 and MDA-MB-231 cell lines. Each matrix represents toxicity based delta score combination plot (red being synergistic and green being antagonistic). The toxicity readout was measured after 96 h from onset of screen disregarding different subsequent combination of drugs in different times to monitor (A) both drugs added together at 0 h, (B) Dactolisib added at the onset of experiment and then trametinib combined after 24 h, (C) Dactolisib added at the onset of experiment and then trametinib combined after 48 h. (PDF 145 kb
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Additional file 8: Figure S4. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:ATP-competitive mTOR inhibitors antagonize the effect of diverse classes of compounds in CAL-51. (A) Scatter plot of DSS scored for combinatory effect of different compounds along with Dactolisib (Y-axis) on CAL-51 cell line compared to their single compound effect (X-axis). The right-hand plot represents the DSS computed using viability assay and the left plot represents cell death assay. Data points with DSS difference more than 10 are highlighted with different colors representing different classes of agents as listed in the color legend. (PDF 118 kb
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Additional file 9: Figure S5. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Cell line specific synergistic drug combination effects. Blue 8 × 8 blue matrices show % viability inhibition whereas red matrices show % cell death as similar represented in Fig. 7 and likewise 7 × 7 matrix represents synergy score. (A) Combining Dactolisib and everolimus resulted in enhancing both viability inhibition and cytotoxicity in CAL-148 and DU4475 cell lines and only increased viability inhibition in MDA-MB-231 but did not show any additive effect in cytotoxicity. (B) The synergistic effect of combining trametinib with iniparib and ponatinib was only seen in DU4475 but not in CAL-148 cell line. (PDF 118 kb
Leena Karhinen - One of the best experts on this subject based on the ideXlab platform.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular Cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Additional file 11: Figure S8. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Time dependent combination effect of Dactolisib and trametinib in DU4475 and MDA-MB-231 cell lines. Each matrix represents toxicity based delta score combination plot (red being synergistic and green being antagonistic). The toxicity readout was measured after 96 h from onset of screen disregarding different subsequent combination of drugs in different times to monitor (A) both drugs added together at 0 h, (B) Dactolisib added at the onset of experiment and then trametinib combined after 24 h, (C) Dactolisib added at the onset of experiment and then trametinib combined after 48 h. (PDF 145 kb
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Additional file 8: Figure S4. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:ATP-competitive mTOR inhibitors antagonize the effect of diverse classes of compounds in CAL-51. (A) Scatter plot of DSS scored for combinatory effect of different compounds along with Dactolisib (Y-axis) on CAL-51 cell line compared to their single compound effect (X-axis). The right-hand plot represents the DSS computed using viability assay and the left plot represents cell death assay. Data points with DSS difference more than 10 are highlighted with different colors representing different classes of agents as listed in the color legend. (PDF 118 kb
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Additional file 9: Figure S5. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Cell line specific synergistic drug combination effects. Blue 8 × 8 blue matrices show % viability inhibition whereas red matrices show % cell death as similar represented in Fig. 7 and likewise 7 × 7 matrix represents synergy score. (A) Combining Dactolisib and everolimus resulted in enhancing both viability inhibition and cytotoxicity in CAL-148 and DU4475 cell lines and only increased viability inhibition in MDA-MB-231 but did not show any additive effect in cytotoxicity. (B) The synergistic effect of combining trametinib with iniparib and ponatinib was only seen in DU4475 but not in CAL-148 cell line. (PDF 118 kb
Agnieszka Szwajda - One of the best experts on this subject based on the ideXlab platform.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular Cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Background Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Molecular cancer, 2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor Dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
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Additional file 11: Figure S8. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Time dependent combination effect of Dactolisib and trametinib in DU4475 and MDA-MB-231 cell lines. Each matrix represents toxicity based delta score combination plot (red being synergistic and green being antagonistic). The toxicity readout was measured after 96 h from onset of screen disregarding different subsequent combination of drugs in different times to monitor (A) both drugs added together at 0 h, (B) Dactolisib added at the onset of experiment and then trametinib combined after 24 h, (C) Dactolisib added at the onset of experiment and then trametinib combined after 48 h. (PDF 145 kb
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Additional file 8: Figure S4. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:ATP-competitive mTOR inhibitors antagonize the effect of diverse classes of compounds in CAL-51. (A) Scatter plot of DSS scored for combinatory effect of different compounds along with Dactolisib (Y-axis) on CAL-51 cell line compared to their single compound effect (X-axis). The right-hand plot represents the DSS computed using viability assay and the left plot represents cell death assay. Data points with DSS difference more than 10 are highlighted with different colors representing different classes of agents as listed in the color legend. (PDF 118 kb
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Additional file 9: Figure S5. of Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
2016Co-Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister WennerbergAbstract:Cell line specific synergistic drug combination effects. Blue 8 × 8 blue matrices show % viability inhibition whereas red matrices show % cell death as similar represented in Fig. 7 and likewise 7 × 7 matrix represents synergy score. (A) Combining Dactolisib and everolimus resulted in enhancing both viability inhibition and cytotoxicity in CAL-148 and DU4475 cell lines and only increased viability inhibition in MDA-MB-231 but did not show any additive effect in cytotoxicity. (B) The synergistic effect of combining trametinib with iniparib and ponatinib was only seen in DU4475 but not in CAL-148 cell line. (PDF 118 kb
