Dataset Information

Jafarnejad2019 - Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma

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. Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.

SUBMITTER: Ahmad Zyoud

PROVIDER: MODEL2003200001 | BioModels | 2020-03-20

REPOSITORIES: BioModels

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

Jafarnejad Mohammad M Sové Richard J RJ Danilova Ludmila L Mirando Adam C AC Zhang Yu Y Yarchoan Mark M Tran Phuoc T PT Pandey Niranjan B NB Fertig Elana J EJ Popel Aleksander S AS

NPJ systems biology and applications 20190816

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 ...[more]

PMID: 31452933

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Project description:Renal cell carcinoma (RCC) is one of the ten most common malignancies. Even though recent paradigm changes led to inclusion of immune checkpoint inhibitor combination therapy in treatment of naive metastatic RCC, insight in the biology and management of RCC would still favour the use of a combination of kinase inhibitors to target multiple pathways, presenting the possibility of enhanced efficacy and reduced development of resistance. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, to identify optimized drug combinations (ODC) in 5 different human RCC lines. This approach requires no a priori mechanistic information on drug mechanism of action, and uses statistical modelling circumventing the need to experimentally screen large numbers of combinations. Different ODC with up to 90% effectivity were obtained for the 5 cell lines, importantly, by combining drug at doses that individually only inhibit 5-25% cell viability. Cell viability was reduced and apoptosis induced, accompanied by a general inhibition of downstream survival and growth promoting effector kinase RPS6. Global phosphoproteomics analysis of the cell lines revealed that in all cases where the ODC showed >50% efficacy, the most active kinases were targets of the selected drugs in the ODC. Interestingly, we observed considerable overlap in the top 20 most active kinases in all 5 cell lines, suggesting a universal ODC might be effective in all cells. Indeed, a combination of erlotinib and dasatinib, targeting EGFR and EPHA2/SRC signaling respectively, combined with AZD4547 or axitinib (targeting VEGFR and FGFR signaling), displayed excellent activity. The effect of the 786-O cell-line specific ODC was analysed in more detail using phosphoproteomics coupled to kinase activity analysis using the INKA pipeline.approaches. As expected, the activity of the main targets of erlotinib and dasatinib was reduced, but the activity of several untargeted kinases, including AXL, PTK2 and MET, remained high or increased, having potential implications for the development of resistance. Addition of crizotinib, targeting MET and PTK2, to the 3-drug ODC but not exchange with axitinib, further enhanced drug combination efficacy. In conclusion, we show that the phenotypic s-FSC method is highly effective in selecting optimized combinations of drugs, and that phosphoproteomics analysis can help further refine the selection of drugs included in the screen or final drug mixture.

Dataset Information

Jafarnejad2019 - Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma

Publications

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

Similar Datasets

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