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

Abstract MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitor...

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Autores principales: Elena M. Tosca, Glenn Gauderat, Sylvain Fouliard, Mike Burbridge, Marylore Chenel, Paolo Magni
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Publicado: Wiley 2021
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spelling oai:doaj.org-article:aa833859fc9044a780546843b278ac282021-11-15T18:41:53ZModeling restoration of gefitinib efficacy by co‐administration of MET inhibitors in an EGFR inhibitor‐resistant NSCLC xenograft model: A tumor‐in‐host DEB‐based approach2163-830610.1002/psp4.12710https://doaj.org/article/aa833859fc9044a780546843b278ac282021-11-01T00:00:00Zhttps://doi.org/10.1002/psp4.12710https://doaj.org/toc/2163-8306Abstract MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small 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 tumor‐in‐host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly‐targeted combination therapies. The population DEB‐based tumor growth inhibition (TGI) model well‐described 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 gefitinib‐resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB‐TGI model allowed to capture gefitinib anticancer activity enhanced by the co‐administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model‐based 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 DEB‐based tumor‐in‐host 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 tumor‐in‐host DEB‐TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.Elena M. ToscaGlenn GauderatSylvain FouliardMike BurbridgeMarylore ChenelPaolo MagniWileyarticleTherapeutics. PharmacologyRM1-950ENCPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 11, Pp 1396-1411 (2021)
institution DOAJ
collection DOAJ
language EN
topic Therapeutics. Pharmacology
RM1-950
spellingShingle Therapeutics. Pharmacology
RM1-950
Elena M. Tosca
Glenn Gauderat
Sylvain Fouliard
Mike Burbridge
Marylore Chenel
Paolo Magni
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
description Abstract MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non‐small 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 tumor‐in‐host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly‐targeted combination therapies. The population DEB‐based tumor growth inhibition (TGI) model well‐described 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 gefitinib‐resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB‐TGI model allowed to capture gefitinib anticancer activity enhanced by the co‐administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model‐based 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 DEB‐based tumor‐in‐host 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 tumor‐in‐host DEB‐TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.
format article
author Elena M. Tosca
Glenn Gauderat
Sylvain Fouliard
Mike Burbridge
Marylore Chenel
Paolo Magni
author_facet Elena M. Tosca
Glenn Gauderat
Sylvain Fouliard
Mike Burbridge
Marylore Chenel
Paolo Magni
author_sort Elena M. Tosca
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher Wiley
publishDate 2021
url https://doaj.org/article/aa833859fc9044a780546843b278ac28
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