Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity
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Authors
Heijink, Anne MargrietEverts, Marieke
Honeywell, Megan E
Richards, Ryan
Kok, Yannick P.
de Vries, Elisabeth G. E.
Lee, Michael J
van Vugt, Marcel A T M
UMass Chan Affiliations
Graduate School of Biomedical SciencesProgram in Molecular Medicine
Program in Systems Biology
Document Type
Journal ArticlePublication Date
2019-08-27Keywords
DDRDNA damage
G3BP2
MK2
cell cycle
checkpoint
cisplatin
mitosis
modeling
systems biology
Cancer Biology
Cell Biology
Cells
Cellular and Molecular Physiology
Genetic Phenomena
Systems Biology
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Show full item recordAbstract
Triple-negative breast cancers (TNBCs) display great diversity in cisplatin sensitivity that cannot be explained solely by cancer-associated DNA repair defects. Differential activation of the DNA damage response (DDR) to cisplatin has been proposed to underlie the observed differential sensitivity, but it has not been investigated systematically. Systems-level analysis-using quantitative time-resolved signaling data and phenotypic responses, in combination with mathematical modeling-identifies that the activation status of cell-cycle checkpoints determines cisplatin sensitivity in TNBC cell lines. Specifically, inactivation of the cell-cycle checkpoint regulator MK2 or G3BP2 sensitizes cisplatin-resistant TNBC cell lines to cisplatin. Dynamic signaling data of five cell cycle-related signals predicts cisplatin sensitivity of TNBC cell lines. We provide a time-resolved map of cisplatin-induced signaling that uncovers determinants of chemo-sensitivity, underscores the impact of cell-cycle checkpoints on cisplatin sensitivity, and offers starting points to optimize treatment efficacy.Source
Cell Rep. 2019 Aug 27;28(9):2345-2357.e5. doi: 10.1016/j.celrep.2019.07.070. Link to article on publisher's site
DOI
10.1016/j.celrep.2019.07.070Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41154PubMed ID
31461651Related Resources
Rights
Copyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2019.07.070
Scopus Count
Except where otherwise noted, this item's license is described as Copyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).