Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma.
Anilides
/ pharmacology
Antibodies, Monoclonal, Humanized
/ pharmacology
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Cell Movement
/ drug effects
Computer Simulation
Drug Resistance, Neoplasm
/ drug effects
Hep G2 Cells
Hepatocyte Growth Factor
/ genetics
Humans
Integrins
/ metabolism
Liver Neoplasms
/ metabolism
Proto-Oncogene Proteins c-met
/ genetics
Pyridines
/ pharmacology
Signal Transduction
/ drug effects
Sorafenib
/ pharmacology
Systems Biology
/ methods
Cancer
Computer modelling
Journal
NPJ systems biology and applications
ISSN: 2056-7189
Titre abrégé: NPJ Syst Biol Appl
Pays: England
ID NLM: 101677786
Informations de publication
Date de publication:
2019
2019
Historique:
received:
11
02
2019
accepted:
01
08
2019
entrez:
28
8
2019
pubmed:
28
8
2019
medline:
28
4
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31452933
doi: 10.1038/s41540-019-0107-2
pii: 107
pmc: PMC6697704
doi:
Substances chimiques
Anilides
0
Antibodies, Monoclonal, Humanized
0
HGF protein, human
0
Integrins
0
Pyridines
0
cabozantinib
1C39JW444G
rilotumumab
51WEW898IJ
Hepatocyte Growth Factor
67256-21-7
Sorafenib
9ZOQ3TZI87
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
29Subventions
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA138264
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA212007
Pays : United States
Déclaration de conflit d'intérêts
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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