Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma.,npj Systems Biology and Applications

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Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma.
npj Systems Biology and Applications ( IF 3.5 ) Pub Date : 2019-08-16 , DOI: 10.1038/s41540-019-0107-2
Mohammad Jafarnejad ₁ , Richard J Sové ₁ , Ludmila Danilova ₂ , Adam C Mirando ₁ , Yu Zhang ₁ , Mark Yarchoan ₃ , Phuoc T Tran _{4,

5} , Niranjan B Pandey ₁ , Elana J Fertig _{1,

2,

6} , Aleksander S Popel _{1,

3}

Affiliation

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.

中文翻译：

肝细胞癌中 HGF/Met 通路的机制详细系统生物学模型。

肝细胞生长因子 (HGF) 通过其受体 Met 发出的信号与肝细胞癌的肿瘤发生和进展有关。 Met 与整合素的相互作用可调节 Akt 和 ERK（细胞外调节激酶）的下游信号传导。在这项研究中，我们开发了 HGF/Met 信号通路的机制详细的系统生物学模型，该模型结合了与整合素的特异性相互作用，以研究整合素结合肽 AXT050 作为单一疗法以及与针对该通路的其他疗法组合的功效。在这里，我们报告，对 AXT050 反应的模拟动力学表明，受体运输足以解释 Met-整合素相互作用对 HGF 信号传导的影响。此外，该模型还预测了 AXT050 与索拉非尼、卡博替尼和利妥木单抗联合用药的患者特异性协同作用和拮抗作用。总体而言，该模型为研究靶向受体酪氨酸激酶的药物与整合素相互作用的功效以及识别患者的协同药物组合提供了一个有价值的框架。

更新日期：2019-08-16

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