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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1012236/full |
| _version_ | 1798045595180466176 |
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| author | Federica Fabro Nynke M. Kannegieter Erik L. de Graaf Karla Queiroz Martine L. M. Lamfers Anna Ressa Sieger Leenstra |
| author_facet | Federica Fabro Nynke M. Kannegieter Erik L. de Graaf Karla Queiroz Martine L. M. Lamfers Anna Ressa Sieger Leenstra |
| author_sort | Federica Fabro |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T23:23:35Z |
| format | Article |
| id | doaj.art-a03d0dd0ba92489c833fc6b7a77ba8fd |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T23:23:35Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a03d0dd0ba92489c833fc6b7a77ba8fd2022-12-22T03:57:23ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.10122361012236Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastomaFederica Fabro0Nynke M. Kannegieter1Erik L. de Graaf2Karla Queiroz3Martine L. M. Lamfers4Anna Ressa5Sieger Leenstra6Department of Neurosurgery, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, NetherlandsPepscope BV, Wageningen, NetherlandsPepscope BV, Wageningen, NetherlandsMIMETAS BV, Oegstgeest, NetherlandsDepartment of Neurosurgery, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, NetherlandsPepscope BV, Wageningen, NetherlandsDepartment of Neurosurgery, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, NetherlandsGlioblastoma 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.https://www.frontiersin.org/articles/10.3389/fonc.2022.1012236/fullglioblastomadrug resistancesmall molecule kinase inhibitorsmechanism of actionkinome activitycell culture models |
| spellingShingle | Federica Fabro Nynke M. Kannegieter Erik L. de Graaf Karla Queiroz Martine L. M. Lamfers Anna Ressa Sieger Leenstra Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in glioblastoma Frontiers in Oncology glioblastoma drug resistance small molecule kinase inhibitors mechanism of action kinome activity cell culture models |
| 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 | glioblastoma drug resistance small molecule kinase inhibitors mechanism of action kinome activity cell culture models |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1012236/full |
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