1Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.
2Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD USA.
NPJ Syst Biol Appl. 2019 Aug 16;5:29. doi: 10.1038/s41540-019-0107-2. eCollection 2019.
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.
肝细胞生长因子（HGF）通过其受体 Met 的信号转导与肝细胞癌的发生和发展有关。研究表明，Met 与整合素的相互作用可以调节下游 Akt 和 ERK（细胞外调节激酶）信号转导。在这项研究中，我们开发了一种机制上详细的 HGF/Met 信号通路系统生物学模型，该模型纳入了与整合素的特定相互作用，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治疗药物联合使用的疗效。在这里，我们报告说，对 AXT050 反应的建模动力学表明，受体运输足以解释 Met-整合素相互作用对 HGF 信号转导的影响。此外，该模型预测了 AXT050 与索拉非尼、卡博替尼和雷莫芦单抗联合使用的患者特异性协同作用和疗效和效力的拮抗作用。总的来说，该模型为研究针对受体酪氨酸激酶与整合素相互作用的药物的疗效以及确定协同药物组合提供了一个有价值的框架。
