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

Summary: 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.: Triple-negative breast cancers show large variation in sensitivity to the chemotherapeutic agent cisplatin that cannot be explained by defects in DNA repair. Heijink et al. conducted a systems-level analysis of cisplatin-induced signal transduction and reveal that signaling dynamics can be used to predict cisplatin sensitivity of TNBC models. Keywords: systems biology, checkpoint, cell cycle, DNA damage, modeling, DDR, cisplatin, G3BP2, MK2, mitosis

Abstract licence: CC BY-NC

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