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Updated: Nov 4, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

10.8K

A systematic analysis of signaling reactivation and drug resistance

Boris N Kholodenko1, Nora Rauch2, Walter Kolch3

  • 1Systems Biology Ireland, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland; Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.

Cell Reports
|May 26, 2021
PubMed

Insights

Drug resistance stems from reactivated signaling pathways. Complete reactivation requires dual pathways, not just feedback loops, informing new drug combination strategies.

Area of Science:

  • Systems Biology
  • Pharmacology
  • Molecular Biology

Background:

  • Drug resistance is a significant challenge in cancer therapy.
  • Reactivation of signaling pathways is a known mechanism of drug resistance.
  • Network topology's role in this reactivation is not fully understood.

Purpose of the Study:

  • To investigate how different biological network structures influence signaling pathway reactivation after drug treatment.
  • To elucidate the mechanisms underlying network-dependent drug resistance.
  • To identify strategies for optimizing drug combinations to overcome resistance.

Main Methods:

  • Analysis of signaling network topologies under simulated drug treatment.
  • Mathematical modeling of pathway dynamics.
  • Experimental validation of predicted resistance mechanisms and drug combinations.

Main Results:

  • Feedback loops alone are insufficient for complete signaling reactivation.
  • Complete reactivation requires at least two distinct pathways (activating and inhibitory) from an upstream protein to a downstream output.
  • Drug-induced target dimerization and alleviation of negative feedback can paradoxically enhance pathway activity.

Conclusions:

  • Network context is crucial for understanding and predicting drug resistance.
  • Dual-pathway reactivation is a key mechanism for complete signaling restoration.
  • Targeted drug combinations, considering network topology and dimerization, can effectively block resistance, as demonstrated with RAF inhibitors against mutant NRAS signaling.
Keywords:
MAPK pathwaysRAF inhibitorsdrug resistancedrug synergykinase inhibitorskinetic modelsmodular response analysisoncogenic RASsignaling networkstargeted therapy

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