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Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity

Heijink, A. M., Everts, M., Honeywell, M. E., Richards, R., Kok, Y. P., de Vries, E. G. E., Lee, M. J. & van Vugt, M. A. T. M., 27-Aug-2019, In : Cell reports. 28, 9, p. 2345-2357.e5 18 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2345-2357.e5
Number of pages18
JournalCell reports
Volume28
Issue number9
Publication statusPublished - 27-Aug-2019

    Keywords

  • DNA-DAMAGE RESPONSE, MESENCHYMAL TRANSITION, INHIBITION, CYCLE, KINASE, WEE1, PROGRESSION, MODULATION, MECHANISMS, RESISTANCE

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