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The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor
Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756857/ https://www.ncbi.nlm.nih.gov/pubmed/31565187 http://dx.doi.org/10.18632/oncotarget.27165 |
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author | Aye, Jamie M. Stafman, Laura L. Williams, Adele P. Garner, Evan F. Stewart, Jerry E. Anderson, Joshua C. Mruthyunjayappa, Smitha Waldrop, Mary G. Goolsby, Caroline D. Markert, Hooper R. Quinn, Colin Marayati, Raoud Mroczek-Musulman, Elizabeth Willey, Christopher D. Yoon, Karina J. Whelan, Kimberly F. Beierle, Elizabeth A. |
author_facet | Aye, Jamie M. Stafman, Laura L. Williams, Adele P. Garner, Evan F. Stewart, Jerry E. Anderson, Joshua C. Mruthyunjayappa, Smitha Waldrop, Mary G. Goolsby, Caroline D. Markert, Hooper R. Quinn, Colin Marayati, Raoud Mroczek-Musulman, Elizabeth Willey, Christopher D. Yoon, Karina J. Whelan, Kimberly F. Beierle, Elizabeth A. |
author_sort | Aye, Jamie M. |
collection | PubMed |
description | Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRβ) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRβ was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRβ inhibitors. |
format | Online Article Text |
id | pubmed-6756857 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-67568572019-09-27 The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor Aye, Jamie M. Stafman, Laura L. Williams, Adele P. Garner, Evan F. Stewart, Jerry E. Anderson, Joshua C. Mruthyunjayappa, Smitha Waldrop, Mary G. Goolsby, Caroline D. Markert, Hooper R. Quinn, Colin Marayati, Raoud Mroczek-Musulman, Elizabeth Willey, Christopher D. Yoon, Karina J. Whelan, Kimberly F. Beierle, Elizabeth A. Oncotarget Research Paper Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRβ) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRβ was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRβ inhibitors. Impact Journals LLC 2019-09-17 /pmc/articles/PMC6756857/ /pubmed/31565187 http://dx.doi.org/10.18632/oncotarget.27165 Text en Copyright © 2019 Aye et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Aye, Jamie M. Stafman, Laura L. Williams, Adele P. Garner, Evan F. Stewart, Jerry E. Anderson, Joshua C. Mruthyunjayappa, Smitha Waldrop, Mary G. Goolsby, Caroline D. Markert, Hooper R. Quinn, Colin Marayati, Raoud Mroczek-Musulman, Elizabeth Willey, Christopher D. Yoon, Karina J. Whelan, Kimberly F. Beierle, Elizabeth A. The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor |
title | The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor |
title_full | The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor |
title_fullStr | The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor |
title_full_unstemmed | The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor |
title_short | The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor |
title_sort | effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic wilms tumor |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756857/ https://www.ncbi.nlm.nih.gov/pubmed/31565187 http://dx.doi.org/10.18632/oncotarget.27165 |
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