Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance

Mol Syst Biol. 2023 Feb 10;19(2):e10988. doi: 10.15252/msb.202210988. Epub 2023 Jan 26.


BRAF is prototypical of oncogenes that can be targeted therapeutically and the treatment of BRAFV600E melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring generates a drug adapted state thought to be involved in acquired resistance and disease recurrence. In this article, we study mechanisms of adaptive rewiring in BRAFV600E melanoma cells using an energy-based implementation of ordinary differential equation (ODE) modeling in combination with proteomic, transcriptomic and imaging data. We develop a method for causal tracing of ODE models and identify two parallel MAPK reaction channels that are differentially sensitive to RAF and MEK inhibitors due to differences in protein oligomerization and drug binding. We describe how these channels, and timescale separation between immediate-early signaling and transcriptional feedback, create a state in which the RAS-regulated MAPK channel can be activated by growth factors under conditions in which the BRAFV600E -driven channel is fully inhibited. Further development of the approaches in this article is expected to yield a unified model of adaptive drug resistance in melanoma.

Keywords: MAPK pathway; allosteric interactions; drug resistance; kinetic modeling; rewiring.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • MAP Kinase Signaling System
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • Melanoma* / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinase Kinases / therapeutic use
  • Mutation
  • Neoplasm Recurrence, Local
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proteomics
  • Proto-Oncogene Proteins B-raf* / genetics
  • Proto-Oncogene Proteins B-raf* / metabolism


  • Mitogen-Activated Protein Kinase Kinases
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • BRAF protein, human