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Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells

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 differ...

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Autores principales: Gautam, Prson, Karhinen, Leena, Szwajda, Agnieszka, Jha, Sawan Kumar, Yadav, Bhagwan, Aittokallio, Tero, Wennerberg, Krister
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862054/
https://www.ncbi.nlm.nih.gov/pubmed/27165605
http://dx.doi.org/10.1186/s12943-016-0517-3
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author Gautam, Prson
Karhinen, Leena
Szwajda, Agnieszka
Jha, Sawan Kumar
Yadav, Bhagwan
Aittokallio, Tero
Wennerberg, Krister
author_facet Gautam, Prson
Karhinen, Leena
Szwajda, Agnieszka
Jha, Sawan Kumar
Yadav, Bhagwan
Aittokallio, Tero
Wennerberg, Krister
author_sort Gautam, Prson
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-016-0517-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-48620542016-05-11 Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells Gautam, Prson Karhinen, Leena Szwajda, Agnieszka Jha, Sawan Kumar Yadav, Bhagwan Aittokallio, Tero Wennerberg, Krister Mol Cancer Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-016-0517-3) contains supplementary material, which is available to authorized users. BioMed Central 2016-05-10 /pmc/articles/PMC4862054/ /pubmed/27165605 http://dx.doi.org/10.1186/s12943-016-0517-3 Text en © Gautam et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Gautam, Prson
Karhinen, Leena
Szwajda, Agnieszka
Jha, Sawan Kumar
Yadav, Bhagwan
Aittokallio, Tero
Wennerberg, Krister
Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
title Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
title_full Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
title_fullStr Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
title_full_unstemmed Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
title_short Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
title_sort identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862054/
https://www.ncbi.nlm.nih.gov/pubmed/27165605
http://dx.doi.org/10.1186/s12943-016-0517-3
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