TY - JOUR T1 - Limited inhibition of multiple nodes in a driver network blocks metastasis JF - bioRxiv DO - 10.1101/2020.06.05.137117 SP - 2020.06.05.137117 AU - Ali E. Yesilkanal AU - Dongbo Yang AU - Payal Tiwari AU - Alan U. Sabino AU - Jiyoung Lee AU - Xiao-He Xie AU - Siqi Sun AU - Christopher Dann AU - Ethan Steinberg AU - Timothy Stuhlmiller AU - Casey Frankenberger AU - Elizabeth Goldsmith AU - Gary L. Johnson AU - Alexandre F. Ramos AU - Marsha R. Rosner Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/07/2020.06.05.137117.abstract N2 - Metastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of its core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stress-regulated MAP kinase network activity, reducing the output to metastatic transcription factor 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: 1) limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells, and 2) 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.Competing Interest StatementThe authors have declared no competing interest. ER -