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CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical...

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Autores principales: Langebäck, Anette, Bacanu, Smaranda, Laursen, Henriette, Mout, Lisanne, Seki, Takahiro, Erkens-Schulze, Sigrun, Ramos, Anderson Daniel, Berggren, Anna, Cao, Yihai, Hartman, Johan, van Weerden, Wytske, Bergh, Jonas, Nordlund, Pär, Lööf, Sara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920357/
https://www.ncbi.nlm.nih.gov/pubmed/31852908
http://dx.doi.org/10.1038/s41598-019-55526-8
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author Langebäck, Anette
Bacanu, Smaranda
Laursen, Henriette
Mout, Lisanne
Seki, Takahiro
Erkens-Schulze, Sigrun
Ramos, Anderson Daniel
Berggren, Anna
Cao, Yihai
Hartman, Johan
van Weerden, Wytske
Bergh, Jonas
Nordlund, Pär
Lööf, Sara
author_facet Langebäck, Anette
Bacanu, Smaranda
Laursen, Henriette
Mout, Lisanne
Seki, Takahiro
Erkens-Schulze, Sigrun
Ramos, Anderson Daniel
Berggren, Anna
Cao, Yihai
Hartman, Johan
van Weerden, Wytske
Bergh, Jonas
Nordlund, Pär
Lööf, Sara
author_sort Langebäck, Anette
collection PubMed
description The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies.
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spelling pubmed-69203572019-12-20 CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance Langebäck, Anette Bacanu, Smaranda Laursen, Henriette Mout, Lisanne Seki, Takahiro Erkens-Schulze, Sigrun Ramos, Anderson Daniel Berggren, Anna Cao, Yihai Hartman, Johan van Weerden, Wytske Bergh, Jonas Nordlund, Pär Lööf, Sara Sci Rep Article The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies. Nature Publishing Group UK 2019-12-18 /pmc/articles/PMC6920357/ /pubmed/31852908 http://dx.doi.org/10.1038/s41598-019-55526-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Langebäck, Anette
Bacanu, Smaranda
Laursen, Henriette
Mout, Lisanne
Seki, Takahiro
Erkens-Schulze, Sigrun
Ramos, Anderson Daniel
Berggren, Anna
Cao, Yihai
Hartman, Johan
van Weerden, Wytske
Bergh, Jonas
Nordlund, Pär
Lööf, Sara
CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
title CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
title_full CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
title_fullStr CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
title_full_unstemmed CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
title_short CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
title_sort cetsa-based target engagement of taxanes as biomarkers for efficacy and resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920357/
https://www.ncbi.nlm.nih.gov/pubmed/31852908
http://dx.doi.org/10.1038/s41598-019-55526-8
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