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Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma

Glioblastoma is the deadliest brain cancer. One of the main reasons for poor outcome resides in therapy resistance, which adds additional challenges in finding an effective treatment. Small protein kinase inhibitors are molecules that have become widely studied for cancer treatments, including gliob...

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Autores principales: Fabro, Federica, Kannegieter, Nynke M., de Graaf, Erik L., Queiroz, Karla, Lamfers, Martine L. M., Ressa, Anna, Leenstra, Sieger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670801/
https://www.ncbi.nlm.nih.gov/pubmed/36408180
http://dx.doi.org/10.3389/fonc.2022.1012236
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author Fabro, Federica
Kannegieter, Nynke M.
de Graaf, Erik L.
Queiroz, Karla
Lamfers, Martine L. M.
Ressa, Anna
Leenstra, Sieger
author_facet Fabro, Federica
Kannegieter, Nynke M.
de Graaf, Erik L.
Queiroz, Karla
Lamfers, Martine L. M.
Ressa, Anna
Leenstra, Sieger
author_sort Fabro, Federica
collection PubMed
description Glioblastoma is the deadliest brain cancer. One of the main reasons for poor outcome resides in therapy resistance, which adds additional challenges in finding an effective treatment. Small protein kinase inhibitors are molecules that have become widely studied for cancer treatments, including glioblastoma. However, none of these drugs have demonstrated a therapeutic activity or brought more benefit compared to the current standard procedure in clinical trials. Hence, understanding the reasons of the limited efficacy and drug resistance is valuable to develop more effective strategies toward the future. To gain novel insights into the method of action and drug resistance in glioblastoma, we established in parallel two patient-derived glioblastoma 2D and 3D organotypic multicellular spheroids models, and exposed them to a prolonged treatment of three weeks with temozolomide or either the two small protein kinase inhibitors enzastaurin and imatinib. We coupled the phenotypic evidence of cytotoxicity, proliferation, and migration to a novel kinase activity profiling platform (QuantaKinome™) that measured the activities of the intracellular network of kinases affected by the drug treatments. The results revealed a heterogeneous inter-patient phenotypic and molecular response to the different drugs. In general, small differences in kinase activation were observed, suggesting an intrinsic low influence of the drugs to the fundamental cellular processes like proliferation and migration. The pathway analysis indicated that many of the endogenously detected kinases were associated with the ErbB signaling pathway. We showed the intertumoral variability in drug responses, both in terms of efficacy and resistance, indicating the importance of pursuing a more personalized approach. In addition, we observed the influence derived from the application of 2D or 3D models in in vitro studies of kinases involved in the ErbB signaling pathway. We identified in one 3D sample a new resistance mechanism derived from imatinib treatment that results in a more invasive behavior. The present study applied a new approach to detect unique and specific drug effects associated with pathways in in vitro screening of compounds, to foster future drug development strategies for clinical research in glioblastoma.
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spelling pubmed-96708012022-11-18 Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma Fabro, Federica Kannegieter, Nynke M. de Graaf, Erik L. Queiroz, Karla Lamfers, Martine L. M. Ressa, Anna Leenstra, Sieger Front Oncol Oncology Glioblastoma is the deadliest brain cancer. One of the main reasons for poor outcome resides in therapy resistance, which adds additional challenges in finding an effective treatment. Small protein kinase inhibitors are molecules that have become widely studied for cancer treatments, including glioblastoma. However, none of these drugs have demonstrated a therapeutic activity or brought more benefit compared to the current standard procedure in clinical trials. Hence, understanding the reasons of the limited efficacy and drug resistance is valuable to develop more effective strategies toward the future. To gain novel insights into the method of action and drug resistance in glioblastoma, we established in parallel two patient-derived glioblastoma 2D and 3D organotypic multicellular spheroids models, and exposed them to a prolonged treatment of three weeks with temozolomide or either the two small protein kinase inhibitors enzastaurin and imatinib. We coupled the phenotypic evidence of cytotoxicity, proliferation, and migration to a novel kinase activity profiling platform (QuantaKinome™) that measured the activities of the intracellular network of kinases affected by the drug treatments. The results revealed a heterogeneous inter-patient phenotypic and molecular response to the different drugs. In general, small differences in kinase activation were observed, suggesting an intrinsic low influence of the drugs to the fundamental cellular processes like proliferation and migration. The pathway analysis indicated that many of the endogenously detected kinases were associated with the ErbB signaling pathway. We showed the intertumoral variability in drug responses, both in terms of efficacy and resistance, indicating the importance of pursuing a more personalized approach. In addition, we observed the influence derived from the application of 2D or 3D models in in vitro studies of kinases involved in the ErbB signaling pathway. We identified in one 3D sample a new resistance mechanism derived from imatinib treatment that results in a more invasive behavior. The present study applied a new approach to detect unique and specific drug effects associated with pathways in in vitro screening of compounds, to foster future drug development strategies for clinical research in glioblastoma. Frontiers Media S.A. 2022-11-03 /pmc/articles/PMC9670801/ /pubmed/36408180 http://dx.doi.org/10.3389/fonc.2022.1012236 Text en Copyright © 2022 Fabro, Kannegieter, de Graaf, Queiroz, Lamfers, Ressa and Leenstra https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Fabro, Federica
Kannegieter, Nynke M.
de Graaf, Erik L.
Queiroz, Karla
Lamfers, Martine L. M.
Ressa, Anna
Leenstra, Sieger
Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma
title Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma
title_full Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma
title_fullStr Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma
title_full_unstemmed Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma
title_short Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma
title_sort novel kinome profiling technology reveals drug treatment is patient and 2d/3d model dependent in glioblastoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670801/
https://www.ncbi.nlm.nih.gov/pubmed/36408180
http://dx.doi.org/10.3389/fonc.2022.1012236
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