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.
Highlights
Cancer is a complex disease marked by heterogeneity
Among the genes most inversely correlated with Raf Kinase Inhibitory Protein (RKIP) was BACH1 (BTB and CNC homology 1), a pro-metastatic, basic leucine zipper transcription factor that is post-translationally inhibited by RKIP via let-7 (Figure 1A; DangiGarimella et al, 2009; Yun et al, 2011)
Over 70 of the motility genes as well as BACH1 that inversely correlate with RKIP in patients were downregulated by RKIP in xenograft tumors, suggesting these genes are transcriptionally regulated by RKIP in TNBC (Figure 1B,C and Figure 1—figure supplement 1C)
Summary
Cancer is a complex disease marked by heterogeneity. For solid tumors, metastatic dissemination of sub-populations of tumor cells throughout the body is primarily responsible for lethality (Weigelt et al, 2005). Metastasis is characterized by many distinct biological processes such as tumor cell invasion, transport in vessels, and colonization at distant sites that involve significant cellular stress. Metastatic progression is further complicated by dynamic changes in tumors that undergo evolutionary change in response to cells and stresses within the microenvironment. Previous approaches to treating metastatic disease have largely been ineffective at preventing resistance or recurrence due to cellular heterogeneity and robust compensatory mechanisms. Targeting individual metastatic pathways at maximum tolerated doses using single or multiple anticancer agents can activate compensatory pathways that eventually overcome treatment (Gallaher et al, 2018; Duncan et al, 2012; Wong et al, 2019). Novel strategies for suppressing metastasis are needed, for cancers such as triple negative breast cancer (ER-, PR-, HER2low; TNBC) that lack effective targeted therapy
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