Program in Systems Biology; Program in Molecular Medicine; Graduate School of Biomedical Sciences
Cancer Biology | Cell Biology | Cells | Cellular and Molecular Physiology | Genetic Phenomena | Systems Biology
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.
DDR, DNA damage, G3BP2, MK2, cell cycle, checkpoint, cisplatin, mitosis, modeling, systems biology
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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/).
DOI of Published Version
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
Heijink, Anne Margriet; Everts, Marieke; Honeywell, Megan E.; Richards, Ryan; Kok, Yannick P.; de Vries, Elisabeth G. E.; Lee, Michael J.; and van Vugt, Marcel A T M, "Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity" (2019). Open Access Articles. 3943.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.