Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition.
Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition.
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DOI：
10.1038/ncomms7139
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发表时间：
2015-02-11
影响因子：
16.6
通讯作者：
Sengupta S
中科院分区：
文献类型：
--
作者：
Goldman A;Majumder B;Dhawan A;Ravi S;Goldman D;Kohandel M;Majumder PK;Sengupta S
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 CD44HiCD24Hi 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. Adaptive resistance is an emerging cause of chemotherapy failure in cancer. Here the authors show that adaptive resistance to taxanes is mediated by the upregulation of SFK/Hck survival signalling, and that sequential administration of taxanes and SFK/Hck inhibition restores tumor cell chemosensitivity.
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影响因子：
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作者：
Paliwal P;Radha V;Swarup G
通讯作者：
Swarup G
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
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作者：
Dawson CC;Intapa C;Jabra-Rizk MA
通讯作者：
Jabra-Rizk MA
影响因子：
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作者：
Araujo JC;Mathew P;Armstrong AJ;Braud EL;Posadas E;Lonberg M;Gallick GE;Trudel GC;Paliwal P;Agrawal S;Logothetis CJ
通讯作者：
Logothetis CJ
影响因子：
4.6
作者：
Fox, Donald T.;Duronio, Robert J.
通讯作者：
Duronio, Robert J.