TY - JOUR
T1 - Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma
AU - Jafarnejad, Mohammad
AU - Sové, Richard J.
AU - Danilova, Ludmila
AU - Mirando, Adam C.
AU - Zhang, Yu
AU - Yarchoan, Mark
AU - Tran, Phuoc T.
AU - Pandey, Niranjan B.
AU - Fertig, Elana J.
AU - Popel, Aleksander S.
N1 - Funding Information:
Part of this research was conducted using computational resources at the Maryland Advanced Research Computing Center (MARCC). This project was supported by grants from NIH U01CA212007 to A.S.P., P.T.T., and E.J.F., as well as R01CA138264 to A. S.P.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070839124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070839124&partnerID=8YFLogxK
U2 - 10.1038/s41540-019-0107-2
DO - 10.1038/s41540-019-0107-2
M3 - Article
C2 - 31452933
AN - SCOPUS:85070839124
SN - 2056-7189
VL - 5
JO - npj Systems Biology and Applications
JF - npj Systems Biology and Applications
IS - 1
M1 - 29
ER -