Development of Fangjiomics for Systems Elucidation of Synergistic Mechanism Underlying Combination Therapy

Abstract

The rapid development of omics technology provides an opportunity for fulfilling the understanding of the synergistic mechanism of combination therapy. However, a systems theory to analyze synergy remains an ongoing challenge. Fangjiomics is a novel systems science based on a holistic theory integrated with reductionism which has been utilized to systematically elucidate the synergistic mechanisms underlying combination therapy using multi-target-, pathway- or network-based quantitative methods. Besides, our ability to understand the polyhierarchical structure in synergy is driven based on multi-level omics data fusion in Fangjiomics. According to the basic principle of "Jun-Chen-Zuo-Shi", further global integration across various omics platforms and phenotype-driven quantitative multi-scale modeling would accelerate development in Fangjiomics-based dissection of synergy in multi-drug combination therapies.

Keywords: Combination therapy; Computational model; Fangjiomics; Omics technology; Synergistic mechanism.

Fig. 1

Pathway-based analysis of synergistic mechanisms. A. Imatinib mesylate (IM) and MK-2206 (an AKT inhibitor) respectively act on the receptor tyrosine kinases (RTKs) and the protein kinase B (ATK) in the same pathway of PI3K to express significant synergistic effects, in which IM plays as a sovereign (Jun) and MK-2206 as a minister (Chen) [24](2017; 23(1):171–80). The characteristic effect of the drug combination on multiple targets in the up-down context of pro-apoptotic pathway represents the “vertical array” mode in Fangjiomics. B. The Venn diagram shows the overlapping and unique of biological pathways respectively targeted by jasminoidin (JA), ursodeoxycholic acid (UA) and the combination (JU). JA acts as a sovereign (Jun), while UA acts as an assistant (Zuo) [26](2011; 667(1–3):278–86).

Fig. 2

Network-based synergistic targets analysis developed in Fangjiomics. A. The synergistic mechanism underlying the cellular response to AMB-LF with general dysregulation of metal ion homeostasis and appropriate cellular stress response networks. Among them, AMB plays a major role as a sovereign (Jun), and LF acts as a minister (Chen) to enhance the efficacy of the sovereign. Arrows represent the direction of regulation, and arrow with blunt end represents inhibitory signal. Yellow color indicates significant increases in the expression of gene or process induced by AMB; red indicates significant decreases in the expression of gene or process induced by AMB; green denotes significant increases in the expression of gene or process induced by AMB-LF combination; purple represents significant increases changes in the expression of gene or process induced by AMB-LF combination. The Figure is modified from the pictures published in Scientific Report [30] (2017; 7: 40232). B. The synergy effect of the combination is mostly attributed from SNX-7081 according to the proteins expression profiles of BRCA1, NCL, NF-kB p100/p52, MYC and CCND1 in MEC1 cell. C. The network with key proteins regulated by the combination of SNX-7081 and 2-Fara A is constructed by STRING 10.5. The combination of SNX-7081 and 2-Fara A accentuated the DNA damage compounded by the loss of checkpoint regulators BRCA1 and CCND1, and trigger the cell death following a loss of MYC and NCL and an accumulation of NFkB2. SNX-7081 acts as a sovereign (Jun), while 2-Fara A acts as a minister (Chen). The Figures B&C are respectively drawn according to the results published in Oncotarget [31] (2015;6(38):40981–97).

Fig. 3

The Fangjiomics-based paradigm for future research on synergistic mechanism of drug combination. After fusion of multi-omics profiles, phenotype-dependent synergistic mechanism can be uncovered according to the basic principle of “Jun-Chen-Zuo-Shi” in Fangjiomics.