A systematic analysis of signaling reactivation and drug resistance

Increasing evidence suggests that the reactivation of initially inhibited signaling pathways causes drug resistance. Here, we analyze how network topologies affect signaling responses to drug treatment, Network dependent drug resistance is commonly attributed to negative and positive feedback loops. However, feedback loops by themselves cannot completely reactivate steady-state signaling. Newly synthesized negative feedback regulators can induce a transient overshoot but cannot fully restore output signaling. Complete signaling reactivation can only occur when at least two routes, an activating and inhibitory, connect an inhibited upstream protein to a downstream output. Irrespective of the network topology, drug-induced over expression or increase in target dimerization can restore or even paradoxically increase downstream pathway activity. Kinase dimerization cooperates with inhibitor-mediated alleviation of negative feedback. Our findings inform drug development by considering network context and optimizing the design drug combinations. As an example, we predict and experimentally confirm specific combinations of RAF inhibitors that block mutant NRAS signaling.

Automated summary

Drug resistance may be caused by the impact of network topology on signal transduction, with key factors including negative and positive feedback loops, but feedback loops alone cannot completely reactivate signal transduction. Complete signal reactivation requires at least two pathways connecting the inhibited upstream protein to downstream output. Drug-induced overexpression or target dimerization can restore or increase downstream pathway activity.