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Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition

Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition toward...

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Autores principales: Goldman, Aaron, Majumder, Biswanath, Dhawan, Andrew, Ravi, Sudharshan, Goldman, David, Kohandel, Mohammad, Majumder, Pradip K., Sengupta, Shiladitya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339891/
https://www.ncbi.nlm.nih.gov/pubmed/25669750
http://dx.doi.org/10.1038/ncomms7139
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author Goldman, Aaron
Majumder, Biswanath
Dhawan, Andrew
Ravi, Sudharshan
Goldman, David
Kohandel, Mohammad
Majumder, Pradip K.
Sengupta, Shiladitya
author_facet Goldman, Aaron
Majumder, Biswanath
Dhawan, Andrew
Ravi, Sudharshan
Goldman, David
Kohandel, Mohammad
Majumder, Pradip K.
Sengupta, Shiladitya
author_sort Goldman, Aaron
collection PubMed
description Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.
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spelling pubmed-43398912015-03-02 Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition Goldman, Aaron Majumder, Biswanath Dhawan, Andrew Ravi, Sudharshan Goldman, David Kohandel, Mohammad Majumder, Pradip K. Sengupta, Shiladitya Nat Commun Article Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer. Nature Pub. Group 2015-02-11 /pmc/articles/PMC4339891/ /pubmed/25669750 http://dx.doi.org/10.1038/ncomms7139 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Goldman, Aaron
Majumder, Biswanath
Dhawan, Andrew
Ravi, Sudharshan
Goldman, David
Kohandel, Mohammad
Majumder, Pradip K.
Sengupta, Shiladitya
Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
title Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
title_full Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
title_fullStr Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
title_full_unstemmed Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
title_short Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
title_sort temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339891/
https://www.ncbi.nlm.nih.gov/pubmed/25669750
http://dx.doi.org/10.1038/ncomms7139
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