Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
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Goldman-2014-Temporally Sequenced.pdf
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Author(s)
Goldman, Aaron
Majumder, Biswanath
Dhawan, Andrew
Ravi, Sudharshan
Goldman, David
Kohandel, Mohammad
Majumder, Pradip K.
Sengupta, Shiladitya
Date Issued
February 2015
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Goldman, Aaron, Biswanath Majumder, Andrew Dhawan, Sudharshan Ravi, David Goldman, Mohammad Kohandel, Pradip K. Majumder, and Shiladitya Sengupta. “Temporally Sequenced Anticancer Drugs Overcome Adaptive Resistance by Targeting a Vulnerable Chemotherapy-Induced Phenotypic Transition.” Nature Communications 6 (February 11, 2015): 6139.
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Final published version
Abstract
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[superscript Hi]CD24[superscript 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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1038/ncomms7139
