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Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities

Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs a...

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Autores principales: Jones, Amber B., Schanel, Taylor L., Rigsby, Mikayla R., Griguer, Corinne E., McFarland, Braden C., Anderson, Joshua C., Willey, Christopher D., Hjelmeland, Anita B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486683/
https://www.ncbi.nlm.nih.gov/pubmed/37681903
http://dx.doi.org/10.3390/cells12172171
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author Jones, Amber B.
Schanel, Taylor L.
Rigsby, Mikayla R.
Griguer, Corinne E.
McFarland, Braden C.
Anderson, Joshua C.
Willey, Christopher D.
Hjelmeland, Anita B.
author_facet Jones, Amber B.
Schanel, Taylor L.
Rigsby, Mikayla R.
Griguer, Corinne E.
McFarland, Braden C.
Anderson, Joshua C.
Willey, Christopher D.
Hjelmeland, Anita B.
author_sort Jones, Amber B.
collection PubMed
description Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined. Therefore, we sought to understand the ability of TTFields to disrupt the growth patterns of and induce kinomic landscape shifts in TMZ-sensitive and -resistant GBM cells. We determined that TTFields significantly decreased the growth of TMZ-sensitive and -resistant cells. Kinomic profiling predicted kinases that were induced or repressed by TTFields, suggesting possible therapy-specific vulnerabilities. Serving as a potential pro-survival mechanism for TTFields, kinomics predicted the increased activity of platelet-derived growth-factor receptor alpha (PDGFRα). We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches.
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spelling pubmed-104866832023-09-09 Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities Jones, Amber B. Schanel, Taylor L. Rigsby, Mikayla R. Griguer, Corinne E. McFarland, Braden C. Anderson, Joshua C. Willey, Christopher D. Hjelmeland, Anita B. Cells Article Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined. Therefore, we sought to understand the ability of TTFields to disrupt the growth patterns of and induce kinomic landscape shifts in TMZ-sensitive and -resistant GBM cells. We determined that TTFields significantly decreased the growth of TMZ-sensitive and -resistant cells. Kinomic profiling predicted kinases that were induced or repressed by TTFields, suggesting possible therapy-specific vulnerabilities. Serving as a potential pro-survival mechanism for TTFields, kinomics predicted the increased activity of platelet-derived growth-factor receptor alpha (PDGFRα). We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches. MDPI 2023-08-30 /pmc/articles/PMC10486683/ /pubmed/37681903 http://dx.doi.org/10.3390/cells12172171 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jones, Amber B.
Schanel, Taylor L.
Rigsby, Mikayla R.
Griguer, Corinne E.
McFarland, Braden C.
Anderson, Joshua C.
Willey, Christopher D.
Hjelmeland, Anita B.
Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities
title Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities
title_full Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities
title_fullStr Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities
title_full_unstemmed Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities
title_short Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities
title_sort tumor treating fields alter the kinomic landscape in glioblastoma revealing therapeutic vulnerabilities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486683/
https://www.ncbi.nlm.nih.gov/pubmed/37681903
http://dx.doi.org/10.3390/cells12172171
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