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Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer

Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but re...

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Autores principales: Buiga, Petronela, Elson, Ari, Tabernero, Lydia, Schwartz, Jean-Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723192/
https://www.ncbi.nlm.nih.gov/pubmed/31357550
http://dx.doi.org/10.3390/genes10080568
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author Buiga, Petronela
Elson, Ari
Tabernero, Lydia
Schwartz, Jean-Marc
author_facet Buiga, Petronela
Elson, Ari
Tabernero, Lydia
Schwartz, Jean-Marc
author_sort Buiga, Petronela
collection PubMed
description Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but resistance to its action frequently develops and limits its therapeutic benefit. Dual-specificity phosphatases (DUSPs) were previously highlighted as central regulators of HER2 signaling; therefore, understanding their role is crucial to designing new strategies to improve the efficacy of Herceptin treatment. We investigated whether inhibiting certain DUSPs re-sensitized Herceptin-resistant breast cancer cells to the drug. We built a series of kinetic models incorporating the key players of HER2 signaling pathways and simulating a range of inhibition intensities. The simulation results were compared to live tumor cells in culture, and showed good agreement with the experimental analyses. In particular, we observed that Herceptin-resistant DUSP16-silenced breast cancer cells became more responsive to the drug when treated for 72 h with Herceptin, showing a decrease in resistance, in agreement with the model predictions. Overall, we showed that the kinetic modeling of signaling pathways is able to generate predictions that assist experimental research in the identification of potential targets for cancer treatment.
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spelling pubmed-67231922019-09-10 Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer Buiga, Petronela Elson, Ari Tabernero, Lydia Schwartz, Jean-Marc Genes (Basel) Article Background: HER2 (human epidermal growth factor 2)-positive breast cancer is an aggressive type of breast cancer characterized by the overexpression of the receptor-type protein tyrosine kinase HER2 or amplification of the HER2 gene. It is commonly treated by the drug trastuzumab (Herceptin), but resistance to its action frequently develops and limits its therapeutic benefit. Dual-specificity phosphatases (DUSPs) were previously highlighted as central regulators of HER2 signaling; therefore, understanding their role is crucial to designing new strategies to improve the efficacy of Herceptin treatment. We investigated whether inhibiting certain DUSPs re-sensitized Herceptin-resistant breast cancer cells to the drug. We built a series of kinetic models incorporating the key players of HER2 signaling pathways and simulating a range of inhibition intensities. The simulation results were compared to live tumor cells in culture, and showed good agreement with the experimental analyses. In particular, we observed that Herceptin-resistant DUSP16-silenced breast cancer cells became more responsive to the drug when treated for 72 h with Herceptin, showing a decrease in resistance, in agreement with the model predictions. Overall, we showed that the kinetic modeling of signaling pathways is able to generate predictions that assist experimental research in the identification of potential targets for cancer treatment. MDPI 2019-07-26 /pmc/articles/PMC6723192/ /pubmed/31357550 http://dx.doi.org/10.3390/genes10080568 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Buiga, Petronela
Elson, Ari
Tabernero, Lydia
Schwartz, Jean-Marc
Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
title Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
title_full Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
title_fullStr Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
title_full_unstemmed Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
title_short Kinetic Modeling of DUSP Regulation in Herceptin-Resistant HER2-Positive Breast Cancer
title_sort kinetic modeling of dusp regulation in herceptin-resistant her2-positive breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723192/
https://www.ncbi.nlm.nih.gov/pubmed/31357550
http://dx.doi.org/10.3390/genes10080568
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