6 research outputs found
Modeling restoration of gefitinib efficacy by co-administration of MET inhibitors in an EGFR inhibitor-resistant NSCLC xenograft model: A tumor-in-host DEB-based approach
MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in nonâsmall cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumorâinâhost modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of polyâtargeted combination therapies. The population DEBâbased tumor growth inhibition (TGI) model wellâdescribed the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinibâresistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEBâTGI model allowed to capture gefitinib anticancer activity enhanced by the coâadministered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The modelâbased comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEBâbased tumorâinâhost framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumorâinâhost DEBâTGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies