Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

Joshua C. Anderson; Christine W. Duarte; Karim Welaya; Timothy D. Rohrbach; Markus Bredel; Eddy S. Yang; Nirmal V. Choradia; Jaideep V. Thottassery; George Yancey Gillespie; James A. Bonner; Christopher D. Willey

doi:10.1016/j.radonc.2014.04.010

Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

Joshua C. Anderson, Christine W. Duarte, Karim Welaya, Timothy D. Rohrbach, Markus Bredel, Eddy S. Yang, Nirmal V. Choradia, Jaideep V. Thottassery, George Yancey Gillespie, James A. Bonner, Christopher D. Willey

Radiation Medicine

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Background and purpose Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines"). Materials and methods Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. Results Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. Conclusion GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.

Original language	English
Pages (from-to)	468-474
Number of pages	7
Journal	Radiotherapy and Oncology
Volume	111
Issue number	3
DOIs	https://doi.org/10.1016/j.radonc.2014.04.010
State	Published - Jun 2014

Bibliographical note

Funding Information:
This project has been funded in whole or in part with Federal Funds from the National Cancer Institute (NCI) , National Institutes of Health , under Contract No. HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We also acknowledge NCI grant P20 CA151129 (GYG), S08-221ST T04 , and the National Brain Tumor Society Mary Catherine Calisto Systems Biology grant.

Keywords

Array profiling
Glioblastoma
Kinomics
Temozolomide
Xenolines

ASJC Scopus subject areas

Hematology
Oncology
Radiology Nuclear Medicine and imaging

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10.1016/j.radonc.2014.04.010

Cite this

Anderson, J. C., Duarte, C. W., Welaya, K., Rohrbach, T. D., Bredel, M., Yang, E. S., Choradia, N. V., Thottassery, J. V., Yancey Gillespie, G., Bonner, J. A., & Willey, C. D. (2014). Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines. Radiotherapy and Oncology, 111(3), 468-474. https://doi.org/10.1016/j.radonc.2014.04.010

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title = "Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines",

abstract = "Background and purpose Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or {"}xenolines{"}). Materials and methods Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation{\textregistered}12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. Results Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. Conclusion GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.",

keywords = "Array profiling, Glioblastoma, Kinomics, Temozolomide, Xenolines",

author = "Anderson, {Joshua C.} and Duarte, {Christine W.} and Karim Welaya and Rohrbach, {Timothy D.} and Markus Bredel and Yang, {Eddy S.} and Choradia, {Nirmal V.} and Thottassery, {Jaideep V.} and {Yancey Gillespie}, George and Bonner, {James A.} and Willey, {Christopher D.}",

note = "Funding Information: This project has been funded in whole or in part with Federal Funds from the National Cancer Institute (NCI) , National Institutes of Health , under Contract No. HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We also acknowledge NCI grant P20 CA151129 (GYG), S08-221ST T04 , and the National Brain Tumor Society Mary Catherine Calisto Systems Biology grant. ",

year = "2014",

month = jun,

doi = "10.1016/j.radonc.2014.04.010",

language = "English",

volume = "111",

pages = "468--474",

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TY - JOUR

T1 - Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

AU - Anderson, Joshua C.

AU - Duarte, Christine W.

AU - Welaya, Karim

AU - Rohrbach, Timothy D.

AU - Bredel, Markus

AU - Yang, Eddy S.

AU - Choradia, Nirmal V.

AU - Thottassery, Jaideep V.

AU - Yancey Gillespie, George

AU - Bonner, James A.

AU - Willey, Christopher D.

N1 - Funding Information: This project has been funded in whole or in part with Federal Funds from the National Cancer Institute (NCI) , National Institutes of Health , under Contract No. HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We also acknowledge NCI grant P20 CA151129 (GYG), S08-221ST T04 , and the National Brain Tumor Society Mary Catherine Calisto Systems Biology grant.

PY - 2014/6

Y1 - 2014/6

N2 - Background and purpose Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines"). Materials and methods Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. Results Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. Conclusion GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.

AB - Background and purpose Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines"). Materials and methods Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling. Results Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance. Conclusion GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.

KW - Array profiling

KW - Glioblastoma

KW - Kinomics

KW - Temozolomide

KW - Xenolines

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Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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