Abstract
Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNFα treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNFα sensitivity of these cell lines. Our models could also predict the combined effects of TNFα and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent.
Highlights
Signaling pathways can generate different cellular responses to the same cytotoxic agents
A quantitative model based on the temporal dynamics of caspases 8 activation was developed to predict fractional killing of cancer cells treated with a cytotoxic agent, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)[9]
We found that these cell lines responded differentially to TNFα(Fig. 1D)
Summary
Signaling pathways can generate different cellular responses to the same cytotoxic agents. The first difference is that we systematically measured thirteen intracellular signals, and compared the ability of each individual signal in predicting cellular sensitivity to TNFα.These signals include site-specific phosphorylations of eight intermediate protein kinases and five downstream effectors, which form a network of signaling cascades (Fig. 1A). We selected these signals because most of them are known to be induced by TNFαand/or other cytotoxic agents (Supplementary Table S1). These three differences allow us to show that early spatiotemporal changes in intermediate signals are predictive of cytotoxic sensitivity to TNFαand co-treatments
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