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NPJ Syst Biol Appl. 2019 Aug 16;5:29. doi: 10.1038/s41540-019-0107-2. eCollection 2019.

Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma.

Author information

1
1Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.
2
2Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD USA.
3
3The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD USA.
4
4Department of Radiation Oncology and Molecular and Radiation Sciences, Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins University School of Medicine, Baltimore, MD USA.
5
5Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Centre and Department of Urology, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD USA.
6
6Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD USA.

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.

KEYWORDS:

Cancer; Computer modelling

Conflict of interest statement

Competing interestsA.S.P. is a co-founder and serves as the CSO and N.B.P. is Head of R&D of AsclepiX TherapeuticsInc. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. The other authors declare no competing interests.

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