Limited inhibition of multiple nodes in a driver network blocks metastasis

Ali Ekrem Yesilkanal, Dongbo Yang, Andrea Valdespino, Payal Tiwari, Alan U. Sabino, Long Chi Nguyen, Jiyoung Lee, Xiao He Xie, Siqi Sun, Christopher Dann, Lydia Robinson-Mailman, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L. Johnson, Alexandre F. Ramos, Marsha R. Rosner

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Article numbere59696
JournaleLife
Volume10
DOIs
StatePublished - May 2021
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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