Abstract
Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. Met interaction with integrins is shown to modulate the downstream signaling to Akt and ERK (extracellular-regulated kinase). In this study, we developed a mechanistically detailed systems biology model of HGF/Met signaling pathway that incorporated specific interactions with integrins to investigate the efficacy of integrin-binding peptide, AXT050, as monotherapy and in combination with other therapeutics targeting this pathway. Here we report that the modeled dynamics of the response to AXT050 revealed that receptor trafficking is sufficient to explain the effect of Met–integrin interactions on HGF signaling. Furthermore, the model predicted patient-specific synergy and antagonism of efficacy and potency for combination of AXT050 with sorafenib, cabozantinib, and rilotumumab. Overall, the model provides a valuable framework for studying the efficacy of drugs targeting receptor tyrosine kinase interaction with integrins, and identification of synergistic drug combinations for the patients.
Highlights
Hepatocyte growth factor (HGF) is an essential growth factor for liver regeneration,[1] embryogenesis,[2] and wound healing.[3]
We develop a mechanistically detailed systems biology model of the HGF/Met signaling pathway with detailed representation of the interactions of α5β1 integrin with Met on the cell surface that allowed us to explore the mechanism of action for AXT050 as monotherapy and in combination with other drugs targeting the HGF pathway
The model accurately captured the experimental data by Barbhuiya et al.[30] based on treatment of HepG2 cells with HGF and increasing levels of AXT050 that resulted in progressive inhibition of pMet, pAkt, and pERK (Fig. 2c)
Summary
Hepatocyte growth factor (HGF) is an essential growth factor for liver regeneration,[1] embryogenesis,[2] and wound healing.[3]. A similar pattern was observed for pAkt. In addition to HGF stimulation alone, data on pAkt, pMEK, pERK, and single and double phosphorylated RSK (pRSK and ppRSK, respectively) were available for HGF treatment along with MEK inhibitor, 3-phosphoinositide-dependent protein kinase-1 (PDK1) inhibitor, or both (Fig. 2a).[33] This resulted in a rich dataset to assist in resolving the strength of feedback and crosstalk signals in the pathway. The model accurately captured the experimental data by Barbhuiya et al.[30] based on treatment of HepG2 cells with HGF and increasing levels of AXT050 that resulted in progressive inhibition of pMet, pAkt, and pERK (Fig. 2c). The model captured the effect of treating cells with a combination of inhibitors of Met and PDK1 showing reduced pAkt in early and late timepoints The effect of this combination on pERK levels was more limited, in agreement with the experimental data. The later timepoint is a npj Systems Biology and Applications (2019) 29
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