Abstract
Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest.
Highlights
Anti-cancer combination therapies are an increasingly promising way to better treat patients, offering an increase in efficacy of drugs, and a means to overcome/avoid resistance to targeted drug therapy
CHARACTERIZING SIGNALING NETWORK RESPONSE TO DIFFERENT. We illustrate this method by application to the analysis of the response of PI3K/PTEN/AKT signaling to a drug combination targeting the HER2 receptor and a protein in the down-stream pathway (DSP), PI3K, which were established to be promising drug targets in both mono- and combination therapy in different cancers [1, 15, 42]
The analysis is based on the kinetic model of Ras/RAF/MEK/ERK and PI3K/PTEN/AKT signaling developed in Ref. [30]
Summary
Anti-cancer combination therapies are an increasingly promising way to better treat patients, offering an increase in efficacy of drugs, and a means to overcome/avoid resistance to targeted drug therapy. To promote a more directed and systematic development of combination therapies, it is necessary to clearly elucidate the underlying mechanisms that drive the advantages of drug combination effect. Considering the risk of increasing toxicity by the use of drug combination therapy, the US food and drug administration (FDA) released drug co-development guidance, which proposed stringent regulatory recommendations for the use of combination strategies [1, 3]. According to these recommendations, there should exist a strong biological rationale for the use of the combinations and proven significant advantages over the use of the drugs as individual agents
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