Modeling of signaling crosstalk-mediated drug resistance and its implications on drug combination
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Xiaoqiang Sun1,2,3, Jiguang Bao4, Zhuhong You5, Xing Chen6, Jun Cui3,7
1Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
2School of Mathematical and Computational Science, Sun Yat-Sen University, Guangzhou, 510000, China
3School of Life Science, Sun Yat-Sen University, Guangzhou, 510275, China
4School of Mathematical Sciences, Beijing Normal University, Beijing, 100875, China
5School of Computer Science and Technology, China University of Mining and Technology, Xuzhou, 221116, China
6School of Information and Electrical Engineering, China University of Mining and Technology, Xuzhou, Jiangsu, 221116, China
7Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, 510060, China
Xing Chen, email: [email protected]
Jun Cui, email: [email protected]
Keywords: signaling crosstalk, drug resistance, drug combination, synergism
Received: June 16, 2016 Accepted: August 26, 2016 Published: August 31, 2016
The efficacy of pharmacological perturbation to the signaling transduction network depends on the network topology. However, whether and how signaling dynamics mediated by crosstalk contributes to the drug resistance are not fully understood and remain to be systematically explored. In this study, motivated by a realistic signaling network linked by crosstalk between EGF/EGFR/Ras/MEK/ERK pathway and HGF/HGFR/PI3K/AKT pathway, we develop kinetic models for several small networks with typical crosstalk modules to investigate the role of the architecture of crosstalk in inducing drug resistance. Our results demonstrate that crosstalk inhibition diminishes the response of signaling output to the external stimuli. Moreover, we show that signaling crosstalk affects the relative sensitivity of drugs, and some types of crosstalk modules that could yield resistance to the targeted drugs were identified. Furthermore, we quantitatively evaluate the relative efficacy and synergism of drug combinations. For the modules that are resistant to the targeted drug, we identify drug targets that can not only increase the relative drug efficacy but also act synergistically. In addition, we analyze the role of the strength of crosstalk in switching a module between drug-sensitive and drug-resistant. Our study provides mechanistic insights into the signaling crosstalk-mediated mechanisms of drug resistance and provides implications for the design of synergistic drug combinations to reduce drug resistance.
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