Limited inhibition of multiple nodes in a driver network blocks metastasis

Elife. 2021 May 11;10:e59696. doi: 10.7554/eLife.59696.


Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here, we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically relevant strategy for anti-metastatic treatment.

Keywords: BACH1; MAPK; cancer biology; drug combinations; human; mathematical modeling; metastasis; mouse; raf kinase inhibitory protein.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Cell Movement
  • Drug Combinations
  • Female
  • Humans
  • MAP Kinase Signaling System
  • Metabolic Networks and Pathways / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Metastasis / prevention & control*
  • Phosphatidylethanolamine Binding Protein / genetics*
  • Signal Transduction / drug effects*


  • Drug Combinations
  • Phosphatidylethanolamine Binding Protein
  • Raf kinase inhibitory protein, mouse

Associated data

  • GEO/GSE128983