Limited inhibition of multiple nodes in a driver network blocks metastasis

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.

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

“…( 196 ) Breast ROCK1 Downstream effector of Rho Activation ChIP, RT-PCR Yesilkanal et al. ( 100 ) Breast BACH1 Gene regulation Repression ChIP, reporter assay Lee et al. ( 196 ) Breast IL11 Inflammation Activation ChIP (MAFF), RT-PCR Moon et al.…”

“…BACH1 promotes the expression of matrix metallopeptidase: it directly activates the expression of MMP1 in breast cancer cells ( 75 ) and possibly MMP9 as well ( 99 ). BACH1 also directly enhances the expression of genes involved in cell motility and invasiveness, including ROCK1 in breast cancer ( 100 ). Therefore, BACH1 promotes the invasiveness of cancer cells by enhancing their ability to degrade extracellular matrix and increasing their motility.…”

A Stochastic Binary Model for Regulation of Gene Expression to Investigate Treatment Effects Targeting RKIP

“…The aforementioned processes can be represented as a system of effective chemical reactions as given at Eqs. (1)(2)(3)(4). We denote a gene product by P and its regulatory site by R. In this manuscript, we consider the particular case of positive regulation of the gene by a transcription factor denoted by T F .…”

“…Despite recent advances in our understanding of cancer biology, the use of quantitative methods to integrate the plethora of generated data to design treatments targeting metastasis is still in its infancy [1,2]. The genotypic variability and intrinsic randomness of biochemical reactions governing epigenetics underpin the multiplicity of cancer cell phenotypes commonly termed as tumor heterogeneity [3][4][5][6][7][8].…”

“…Then, we build upon the previous analysis to design an enhanced treatment enabling a faster response with reduced heterogeneity that is independent of the pre-treatment time scales. The enhanced treatment is based on reduced drug dosages to reduce the chances of toxicity and emergence of resistance caused by compensatory effects [1,2].…”