Biological Sciences Division
Published May 11, 2021 | Version v1
Journal article Open

Limited inhibition of multiple nodes in a driver network blocks metastasis

Creators

  • 1. University of Chicago
  • 2. University of São Paulo
  • 3. University of North Carolina at Chapel Hill
  • 4. UT Southwestern

Description

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.

Data availability

RNA sequencing data have been deposited in GEO under the accession code GSE128983.

The following data sets were generated:

Yesilkanal AE Rosner M (2019) NCBI Gene Expression Omnibus ID GSE128983. Gene expression data from BM1 (1833) tumors that are wild type or overexpressing RKIP in a xenograft mouse model. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE128983

The following previously published data sets were used:

Gao J Aksoy BM Dogrusoz U Dresdner G Gross B Sumer SO Sun Y Jacobsen A Sinha R Larsson E Cerami E Sander C Schultz N (2013) cBioPortal, The Cancer Genome Atlas (TCGA Firehose Legacy) ID www.cbioportal.org/. The Cancer Genome Atlas (TCGA). https://www.cbioportal.org/

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Additional details

Identifiers

DOI
10.7554/eLife.59696
Other
oai:uchicago.tind.io:9930

Funding

National Institutes of Health
R01 GM121735-01
National Institutes of Health
CA058223
University of Chicago
Rustandy Fund
University of Chicago
Women's Board Grants Fund
University of Sao Paulo
Use of Intelligent Systems
University of São Paulo
18.5.245.86.7
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
88881.062174/2014-01
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Ben May Department for Cancer Research