Limited inhibition of multiple nodes in a driver network blocks metastasis
- University of Chicago, United States
- University of São Paulo, Brazil
- University of North Carolina at Chapel Hill, United States
- University of Texas Southwestern Medical Center, United States
Abstract
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.
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The Cancer Genome Atlas (TCGA)cBioPortal, The Cancer Genome Atlas (TCGA, Firehose Legacy).
Article and author information
Author details
Funding
National Institutes of Health (R01 GM121735-01)
- Marsha R Rosner
National Institutes of Health (CA058223)
- Gary L Johnson
Rustandy Fund for Innovative Cancer Research
- Marsha R Rosner
University of Chicago Women's Board Grants Fund
- Ali Ekrem Yesilkanal
University of Sao Paulo (Use of Intelligent Systems,18.5.245.86.7)
- Alexandre F Ramos
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88881.062174/2014-01)
- Alexandre F Ramos
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Alan U Sabino
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal protocols related to mouse experiments were approved by the University of Chicago Institutional Animal Care and Use Committee (IACUC #72228).
Copyright
© 2021, Yesilkanal et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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