ArticleeLife2021
Limited inhibition of multiple nodes in a driver network blocks metastasis.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 33 citations in OpenAlex.
- Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ.Nature cell biology · 2026Article
- A control theoretical approach to gene regulation reveals quantitative constraints for dynamic homeostasis in stochastic gene expression.Biochimica et biophysica acta. Molecular basis of disease · 2026Article
- Rho/PAK signaling: a key driver of anthracycline and taxane resistance in breast cancer.Medical oncology (Northwood, London, England) · 2026Review
- The Multifaceted Roles of BACH1 in Disease: Implications for Biological Functions and Therapeutic Applications.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity.Journal of the Royal Society, Interface · 2023Article
- TAOK3 limits age-associated inflammation by negatively modulating macrophage differentiation and their production of TNFα.Immunity & ageing : I & A · 2023Article
- Rational combinations of targeted cancer therapies: background, advances and challenges.Nature reviews. Drug discovery · 2023Review
- Kinome inhibition states and multiomics data enable prediction of cell viability in diverse cancer types.PLoS computational biology · 2023Article
- Manipulating RKIP reverses the metastatic potential of breast cancer cells.Frontiers in oncology · 2023Article
- Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Harnessing RKIP to Combat Heart Disease and Cancer.Cancers · 2022Review
- Adaptive chromatin remodeling and transcriptional changes of the functional kinome in tumor cells in response to targeted kinase inhibition.The Journal of biological chemistry · 2022Review
- A Stochastic Binary Model for the Regulation of Gene Expression to Investigate Responses to Gene Therapy.Cancers · 2022Article
- New strategies for targeting kinase networks in cancer.The Journal of biological chemistry · 2021Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.