Abstract
Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.
Highlights
Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect
The anti-proliferative effect of a drug or drug combination was measured by its induced reduction of the integrated phosphorylated ERK (ppERK) level for the following reason: The level of cell proliferation is linked to DNA synthesis, which is positively associated with the level of the integrated ERK2 activity[47], while the latter is correlated to the integrated ppERK level
In simulating the regulation of EGFR-ERK signaling by phosphatases, we found that increasing PP2A level from 30000 to 60000 molecules/cell induces little changes in the peak amplitude but significantly reduces the duration of ERK activation (Supplementary Figure S3), while increasing MKP3 level from 9 × to 1.5 × molecules/cell significantly alters the peak amplitude and substantially reduces the duration of ERK activation (Supplementary Figure S4), which are consistent with the results of a reported simulation study showing that the duration of ERK activation is sensitive only to phosphatase reactions on MEK whereas the amplitude is most sensitive to phosphatase reactions on ERK50
Summary
Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. We developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Simulation of drug-targeted pathways is potentially useful for predicting CIs17,26, as demonstrated by the successful applications of the chemogenomic profile based models[27,28] and the statistically-inferenced network models[29,30] for the prediction of synergistic effects of drug combinations. The concentration(s) of a drug or drug combination that induces 90% reduction of the integrated ppERK level was used to measure the GI50 value
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