Research ArticleCancer therapy

Modeling chemotherapy-induced stress to identify rational combination therapies in the DNA damage response pathway

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Sci. Signal.  24 Jul 2018:
Vol. 11, Issue 540, eaat0229
DOI: 10.1126/scisignal.aat0229

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Modeling drug-chemotherapy combinations

Pharmacological inhibitors of DNA repair pathways can enhance the efficacy of chemotherapy. Finding those combinations that are most effective in a certain cancer type or exploit vulnerabilities therein is key to improving clinical outcomes. Alkan et al. incorporated various molecular, biochemical, and cellular parameters into a model of cancer cell responses to various chemotherapies to predict and then test the efficacy of combined DNA repair inhibition. Among the expected synergy of chemotherapy with an inhibitor of the kinase ATR, both in culture and in vivo using delayed-release liposome technology, there were some unexpected differences in outcome when applying low-dose versus high-dose chemotherapy regimens. These findings show how modeling in cells can both help inform therapeutic development and reveal new biology to investigate further.

Abstract

Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multiscale computational model that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calibrated on extensive data from U2OS osteosarcoma cells, including the cell cycle distribution of the initial cell population, signaling data measured by Western blotting, and cell fate data in response to chemotherapy treatment measured by time-lapse microscopy. The resulting mechanistic model predicted the cellular responses to chemotherapy alone and in combination with targeted inhibitors of the DNA damage response pathway, which we confirmed experimentally. Computational models such as the one presented here can be used to understand the molecular basis that defines the complex interplay between cell survival and cell death and to rationally identify chemotherapy-potentiating drug combinations.

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