Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity
AuthorsHeijink, Anne Margriet
Honeywell, Megan E.
Kok, Yannick P.
de Vries, Elisabeth G. E.
Lee, Michael J.
van Vugt, Marcel A T M
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Program in Molecular Medicine
Program in Systems Biology
Cellular and Molecular Physiology
MetadataShow full item record
AbstractTriple-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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41154
RightsCopyright 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/).
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/).