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

Federica Fabro, Nynke M. Kannegieter, Erik L. de Graaf, Karla Queiroz, Martine L.M. Lamfers, Anna Ressa, Sieger Leenstra*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number1012236
JournalFrontiers in Oncology
Volume12
DOIs
Publication statusPublished - 3 Nov 2022

Bibliographical note

Funding Information:
This research was funded by the European Union’s Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Actions (No. 766069 GLIOTRAIN). This project was supported at Mimetas by an innovation credit (IK17088) from the Ministry of Economic Affairs and Climate of Netherlands.

Publisher Copyright:
Copyright © 2022 Fabro, Kannegieter, de Graaf, Queiroz, Lamfers, Ressa and Leenstra.

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