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

被引:184
作者
Goldman, Aaron [1 ,2 ,3 ]
Majumder, Biswanath [4 ,5 ]
Dhawan, Andrew [6 ]
Ravi, Sudharshan [3 ]
Goldman, David
Kohandel, Mohammad [7 ]
Majumder, Pradip K. [5 ]
Sengupta, Shiladitya [1 ,2 ,3 ,8 ]
机构
[1] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[2] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA
[3] Brigham & Womens Hosp, Dept Med, Div Biomed Engn, Boston, MA 02115 USA
[4] India Innovat Res Ctr, Bangalore 560099, Karnataka, India
[5] Narayana Nethrayala, Mitra Biotech Pvt Ltd, Bangalore 560099, Karnataka, India
[6] Queens Univ, Sch Med, Kingston, ON K7L 3N6, Canada
[7] Univ Waterloo, Dept Appl Math, Waterloo, ON N2L 3G1, Canada
[8] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA
基金
加拿大自然科学与工程研究理事会;
关键词
METASTATIC BREAST-CANCER; EXPRESSION; CAVEOLIN-1; DASATINIB; CELLS; P73; CARBOPLATIN; ACTIVATION; MECHANISMS; CARCINOMA;
D O I
10.1038/ncomms7139
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:13
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